Pyrimidal [2,3,d]Pyrimidin-4(3H)-ones as antiallergy agents

ABSTRACT

Fused heterocyclic ring systems in which a quinoline or a pyridine component is &#34;fused&#34; to a pyrimidine having a 2-methyl, 2-ethyl, or 2-acetyl group and a 4-keto group, and to similar ring systems in which a quinoline, a naphthalene or a pyridine component is &#34;fused&#34; to a pyrimidine having a 2-carboxy group and a 4-keto group, derivatives, and pharmaceutically-acceptable cationic salts thereof, and their use as antiallergy agents, and intermediates therefor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of application Ser. No. 786,185 filedApr. 11, 1977 which in turn is a division of application Ser. No.667,515 filed Mar. 16, 1976 and now U.S. Pat. No. 4,044,134 which, inturn, is a division of application Ser. No. 485,945 filed July 5, 1974and now U.S. Pat. No. 3,974,161 which, in turn, is acontinuation-in-part of application Ser. No. 444,138 filed Feb. 20, 1974and now abandoned which, in turn, is a continuation-in-part ofapplication Ser. No. 351,025 filed Apr. 13, l973 and now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to fused heterocyclic ring systems in which aquinoline, a naphthalene or a pyridine ring system is fused to a2-methyl-, 2-ethyl, or 2-acetyl pyrimidine-4(3H)-one or to apyrimidine-2-carboxylic acid 4(3H)-one or a derivative thereof, andtheir use as anti-allergy agents. More particularly, it relates to2-alkylpyrimido[4,5-b]quinolin-4(3H)-ones,2-alkylpyrido[4,5-b]pyrimidon-4(3H)-ones wherein alkyl is methyl orethyl, and the corresponding 2-acetyl derivatives,pyrimido[4,5-b]quinolin-4(3H)-ones-2-carboxylic acids,benzo[g]quinazolin-4(3H)-one-2-carboxylic acids, andpyrido-[2,3-d]pyrimidin-4(3H)-one-2-carboxylic acids; esters, amides,and pharmaceutically-acceptable salts thereof which are useful asinhibitors of allergic reactions, and especially of allergic bronchialasthma.

A number of pyrimido[4,5-b]quinolines (1,3-diazo-acridines) aredescribed in the art (J. Chem. Soc., 727 (1927); J. Hetero Chem. 7, 99(1970); J. Am. Chem. Soc. 78, 5108 (1956); and J. Chem. Soc., 552(1948). However, none of them contain a carboxy group or functionalderivative thereof, i.e., an ester, amide, acid chloride, with theexception of 2,4-dihydroxy-pyrimido[4,5-b]quinoline-5-carboxylic acid,its methyl ester, amide and acid chloride;1,3-dimethyl-1,2,3,4-tetrahydro-pyrimido[4,5-b]quinolin-2,4-dione-5-carboxylicacid methyl ester; and10-methyl-2,3,4,10-tetrahydro-pyrimido[4,5-b]quinolin-2,4-dione-5-carboxylicacid and its methyl ester. The products were investigated as potentialriboflavin antagonists, Taylor et al., J. Am. Chem. Soc. 78, 5108 (1956)describe 2-methylpyrimido[4,5-b]quinolin-4(3H)-one. No 2-carboxysubstituted derivatives are described in the literature.

The known pyrimido[4,5-b]quinolin-4(3H)-one when tested by the passivecutaneous anaphylaxis (PCA) test described herein affords only 33%protection in rats at 3.0 mg./kg. via the intravenous route ofadministration. It is, relative to the compounds of this invention, ofmarginal value as an antiallergy agent.

In the benzo[g]quinazolin-4(3H)-one series of compounds of formula II,no analogs wherein a carboxy group (or an ester or amide thereof) isattached directly to the nucleus appear to have been described in theart. However, 2-carbethoxymethylbenzo[g]quinazolin-4(3H)-one isdescribed by Reid et al., Ber. 96, 1218 (1963). No utility is reportedfor the compound It afforded 49% protection in the PCA test whenadministered intravenously at 3.0 mg./kg. Upon acid hydrolysis itundergoes facile decarboxylation at room temperature to2-methylbenzo[g]quinazolin-4(3H)-one (Reid et al., Ber. 95, 3042, 1962)which shows little or no activity in the PCA test.

Benzo[g]quinazolin-4(3H)-one, the compound related to formula II, isreported in Indian Patent No. 74,146, March 2, 1963 [C.A. 60, 1773f,1964) to be active as a bronchodilator. When tested in the PCA testdescribed below it was observed to provide 31% protection in rats at 3.0mg./kg. by the intraveneous route of administration. It is, at best, ofmarginal value in the treatment of bronchial allergies.

The preparation of pyrido[2,3-d]pyrimidines containing a 5-carboxy or5-carbalkoxy group is desscribed by Fatutta, Cazz. Chom. Ital. 93, (5),576-84 (1963); C.A. 59, 6401 (1963). No utility is reported for theproducts. Mulvey et al., J. Org. Chem. 29, 2903-7 (1964) report thesynthesis of pyrido[2,3-d]pyrimidines having a 6-carboxy, 6-carboxamido,or 6-carbalkoxy group. No reports ofpyrido[2,3-d]pyrimidin-4(3H)-one-2-carboxylic acids, esters, or amidesof formula III below appear in the literature. The preparation of2-methylpyrido[2,3-d]pyrimidin-4(3H)-one and its use as a saluretic andcirculatory stimulating agent is described in South African Patent6902561, granted Oct. 21, 1969 (C.A. 72, 125071s, 1970).

Allergic reactions, the symptoms resulting from an antigen antibodyinteraction, manifest themselves in a wide variety of ways and indiffusely different organs and tissues. One of the most disabling anddebilitating of the allergic reactions is asthma, a functional conditionof the bronchi characterized by periodic and spasmodic attacks ofbreathlessness, wheezing, coughing, and expectoration of mucous.

Efforts to discover medicinal agents to alleviate the symptoms of theabnormal physiologic state have been extensive. As early as 1910,Metthews, Brit. Med. J., 1, 441 (1910) reported the bronchodilatoreffects of epinephrine. Since then, Chen and Schmidt, J. Pharmacol.Exper. Therap., 24, 339 (1924) reported the use of the alkaloidephedrine as an orally efficacious bronchodilator with the same spectrumof activity as epinephrine. In 1940, Konzett, Arch. Exp. Path. Pharmak.197, 27 (1940) outlined the effects of the potent aerosol bronchodilatorisoproterenol. Cullum et al., Brit. J. Pharmacol. Exp. 35, 141 (1969)reported the pharmacology of solbutamol, a potent bronchodilator ofprolonged duration, and active via both oral and aerosol administration.Many bronchodilator preparations contain theophylline. These aregenerally less potent than the sympathomimetic amines such asisoproterenol and solbutamol, and are ineffective in aerosoladministration.

Recently, Cox and co-workers, Adv. in Drug Res., 5, 115 (1970) describedthe pharmacology of disodium cromoglycate[1,3-bis-(2-carboxychromon-5-yloxy)-2-hydroxypropane, Intal], an agentuseful in the treatment of bronchial asthma. It is not a bronchodilatorbut mediates its therapeutic effects by a unique mechanism of action. Itsuffers from the lack of oral efficacy and, for optimum results, isadministered by inhalation as a solid inhalant.

Although the aforementioned agents represent outstanding contributionstoward the treatment of asthma, many of them exert the undesired sideeffect of cardiac stimulation

SUMMARY OF THE INVENTION

It has now been found that fused pyrimidines having the formulae##STR1## and the pharmaceutically-acceptable cationic salts thereofexert potent allergy effects in mammals, including man, by an Intal-likemechanism. In contrast to Intal, many of these compounds are effectivevia intraperitioneal and oral administration, as well as by inhalationand intravenous administration.

In the above formulae:

R is selected from the group consisting of methyl, ethyl, acetyl, andCOR° wherein R° is selected from the group consisting of hydroxy,alkoxy, hydroxyalkoxy, amino, hydroxyamino;

Y is selected from the group consisting of (a) hydrogen and (b) alkyl,carbalkoxyalkyl, carboxyalkyl,--(CH₂)_(m) --O--CO--C₆ H₅ and (CH₂)_(m)--O--CO-alkyl;

with the proviso that when R° is amino or hydroxyamino, Y is hydrogen

m is an integer from 2 up to, and including, 4;

R₁ is selected from the group consisting of hydrogen, alkyl and phenyl;

each of R₂, R₃, R₄, and R₅ is selected from the group consisting ofhydrogen, alkyl, alkoxy, halo, benzyloxy, hydroxy, thiol, alkanoyloxy,benzoyloxy, methylthio, methylsulfinyl, benzylthio and benzylsulfinyl;

R₂ and R₃, R₃ and R₄ when taken together are alkylenedioxy and areselected from the group consisting of methylenedioxy and ethylenedioxy.

The terms "alkyl," "alkanoyloxy" and "alkoxy" as used herein includealkyl, alkanoyloxy and alkoxy groups of from 1 up to, and including, 4carbon atoms; the term "hydroxyalkoxy" includes hydroxyalkoxy groupshaving from 2 up to, and including, 4 carbon atoms; and the term"carbalkoxy" includes carbalkoxy groups having from 2 up to, andincluding, 5 carbon atoms. The term "halo" includes chloro, bromo,fluoro, and iodo.

Compounds of the above formulae are, except for those of formula Iwherein Y is hydrogen, R is methyl and each of R₁ -R₅ is hydrogen andthose of formula III wherein R is methyl and each of R₂ -R₄ is hydrogen,new compounds.

By the term "pharmaceutically-acceptable cationic salts" is intendedsalts such as the alkali metal salts, e.g., sodium and potassium;alkaline earth metal salts such as calcium and magnesium; aluminumsalts; ammonium salts; and salts with organic bases, e.g., amines suchas triethylamine, tri-n-butylamine, piperidine, triethanolamine,diethylaminoethylamine, N,N' -dibenzylethylenediamine and pyrrolidine.

The following compounds are of particular interest to this invention:

Formula I: R is CH₃ or COR° wherein R° is alkoxy or hydroxy; each R₁,R₂, and R₅ is hydrogen; and R₃ and R₄ are hydrogen, hydroxy, or alkoxy;provided that when one of R₃ or R₄ is hydroxy, the other is alkoxy.

Formula II: R is COR" wherein R" is hydroxy; R₂ is hydrogen; and each ofR₃ and R₄ is alike and is hydrogen or alkoxy.

Formula III: R is COR° is hydroxy or alkoxy; R₂ is hydrogen; and each ofR₃ and R₄ is alike and is hydrogen or alkoxy.

Special interest exists in the following compounds of formula I:

    ______________________________________                                        R                R.sub.1 R.sub.2                                                                             R.sub.3                                                                             R.sub.4                                                                             R.sub.5                            ______________________________________                                        COR° ;    H       H     OCH.sub.3                                                                           OCH.sub.3                                                                           H                                  R° = OH,  H       H     OH    OCH.sub.3                                                                           H                                  alkoxy           H       H     OCH.sub.3                                                                           OH    H                                  ______________________________________                                    

Compounds of formulae I, II, and III wherein R is carbalkoxy are alsovaluable intermediates for production of compounds wherein R is carboxyor carbamyl. This is especially true of formula II compounds since thosewherein R is carbalkoxy appear of marginal interest as antiallergyagents.

Compounds wherein any of R₂ -R₅ is benzyloxy, benzylthio or methylthio,serve as intermediates for compounds wherein the R group is hydroxy,alkanoyloxy thiol, methylsulfinyl, or benzylsulfinyl.

The antiallergy property of the compounds of this invention is evaluatedby the passive cutaneous anaphylaxis (PCA) test (Ovary, J. Immun. 81,355, 1958). In the PCA test, normal animals are injected intradermally(i.d.) with antibodies contained in serum obtained from activelysensitized animals. The animals are then challenged intravenously withantigen mixed with a dye such as Evans' Blue. The increased capillarypermeability caused by the antigen-antibody reaction causes the dye toleak from the site of the antibody injection. The test animals are thenasphyxiated and the intensity of the reaction determined by measuringthe diameter and intensity of the blue coloration on the inner surfaceof the animals skin.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention can be prepared by a variety of methods.Since structures I, II and III have in common the fused pyrimidine ring,the same reactions can be used to complete this portion of eachstructure. Similarly, the fused pyridine rings of structures I and IIIcan be obtained by the same type of reaction using, of course, theappropriate precursor in each instance.

Compounds of formula I (R ═ COR°) can be prepared by methods in whichuse is made of the intact carbocyclic ring and the quinoline andpyrimidine systems built up in many ways. These methods have, as acommon ground, the construction of the 2-aminoquinoline-3-carboxamide,or 3-carboxy acid or ester thereof, from the intact carbocyclic ring andsubsequent use of the quinoline system as a basis for building up thepyrimidine ring. The general scope of these methods is summarized in thesequence below wherein R' represents hydroxy, alkoxy and amino: ##STR2##

The preferred process on the basis of yield and quality of the finalproduct of formula I is illustrated by Route A. Alternate methods, e.g.,Route B, can also be used as is discussed below.

In each of Routes A and B, the condensation involves the carbocyclicaldehyde or ketone with an active methylene nucleophile. The requisitecarbocyclic aldehydes or ketone reactants are known materials or areprepared by methods described in the art. By "active methylene"nucleophile is meant a compound having a relatively acidic methylenegroup; that is, a methylene group linked to one, and preferably two,electron-withdrawing groups such as --CN, --COCI, --C(NH)NH₂, COR',--C(NH)--O--alkyl and --CO--alkyl.

The condensation is conducted in the presence of a reaction-inertsolvent; that is, a solvent which is not changed as a result of thereaction even though it may participate in the reaction in the role of acatalyst or in salt formation with a reactant or product.

Suitable solvents are alkanols, such as methanol, ethanol, isopropanol,n-butanol and n-hexanol; chlorinated solvents such as methylenechloride, ethylene chloride, chloroform and carbon tetrachloride;pyridine; aromatic hydrocarbons such as benzene, toluene, xylene;hexane; and N,N'-di-methylformamide. Other solvents are found by simpleexperimentation. Methanol is a preferred solvent, especially when usingpiperidine as catalyst, because, of the satisfactory yields, ease ofseparation and purity of products. A solvent system of piperidine andpyridine is frequently a useful system.

A catalyst is often used to facilitate the condensation even when thenucleophiles possess two activating groups as do derivatives ofcyanoacetic acid. Suitable catalysts are ammonia, primary, secondary,and tertiary amines, such as n-butylamine, diethylamine, triethylamine,pyridine, piperidine, pyrrolidine, alkali metal alkoxides and fluorides,stannous fluoride, and basic ion-exchange resins of the amine type,e.g., Amberlite IR-45 (a weakly basic polystyrene with polyamine groupsavailable from Rohm & Haas Co.) and De-Acidite G (polystyrene resin withdiethylamino groups; available from the Permutit Co., Ltd., London).

The amount of catalyst used is not critical but can vary over a widerange, i.e., from about 0.1% to about 100% by weight based upon thecarbocyclic aldehyde reactant. The favored range of catalyst is fromabout 10% to about 30% by weight of the carbocyclic aldehyde reactant.

The reaction is conducted at a temperature of from about 0° C. to about50° C. and generally at about ambient temperature for periods of fromabout one-fourth to five hours. The products generally separate from thereaction mixtures as solids and are recovered by filtration. Those whichdo not separate as solids are recovered by evaporation of the solvent orby pouring into a large volume of a non-solvent for the product.

The use of an o-nitrobenzaldehyde or an R₁ -(2-nitrophenyl) ketone asthe reactant (Route A) produces an α-cyano-β-(2-nitrophenyl)acrylamidederivative, e.g., an amide when R' of the active methylene reactant isNH₂, which must subsequently be reduced and cyclized to provide thedesired 2-aminoquinoline-3-carboxylic acid derivative. Reduction (of thenitro group to an amino group) is accomplished by a variety of reagents.In brief any reagent which will selectively or preferentially reduce thenitro group to an amino group can be used. Representative of suchreagents are metalacid combinations such as iron-acetate acid,iron-hydrochloric acid, tin or stannous chloride-hydrochloric acid,zinc-hydrochloric acid, zinc dustalkali; and catalytic hydrogenationusing catalysts such as platinum, palladium and Raney nickel.

The reduced product appears to cyclize immediately, or almostimmediately, to provide the 2-aminoquinoline-3-carboxylic acidderivative.

When using an o-aminobenzaldehyde as reactant (Route B) the condensationproduct with the cyanoacetic acid derivative cyclizes at a very rapidrate to the 2-aminoquinoline-3-carboxylic acid derivative as noted abovefor the reaction product of Route A.

Formation of the fused pyrimidine ring with its 2-carboxylic acidderivative (ester or amide) substituent can be accomplished by a numberof methods. For convenience, these methods are considered on the basisof the structure of reactant W-Z which contributes the one-carbonfragment to complete the pyrimidine ring system upon the appropriate2-aminoquinoline-3-carboxylic acid derivative:

(1) Reaction of a 2-aminoquinoline-3-carboxamide (formula V, R'═NH₂)with:

(a) a dialkyl oxalate;

(b) a monoacid halide (chloride, bromide) of a half-alkyl oxalic acidester;

(c) an alkyl cyanoformate;

(d) a dialkyl ester of monoiminooxalic acid (a carbalkoxy formimidate);

(e) an alkyl ester of oxamidic acid;

(f) 1-cyanoformamide;

(g) cyanogen; and

(h) 1-carbalkoxyformamidine; or

(2) Reaction of an alkyl 2-aminoquinoline-3-carboxylate with:

(a) a 1-carbalkoxyformamidine.

Reactant W-Z (an oxalic acid derivative) of the step common to Routes Aand B provides the one-carbon fragment needed to complete the fusedpyrimidine ring. It may, depending upon choice of reactants, alsoprovide the --NH group. It represents cyanogen and W-COR° wherein W is--COCl, --CN, --COR°, --CO-alkyl, --C(NH)NH₂ and --C(NH)O--alkyl. WhenW-Z is an alkyl ester of oxamidic acid, e.g., H₅ C₂ OOC-CONH₂, thecyclization reaction occurs so as to produce the amide (R═CONH₂) offormula I.

It is evident that one of the two reactants in the final step of RoutesA and B above must provide the --NH moiety. When the reactant upon whichthe fused pyrimidine ring is to be formed contains a carboxamide group(e.g., formula V wherein --COR' is --CONH₂), reactant W-Z can be any ofthe substances enumerated above; i.e., cyanogen or W-COR°. However, whenthe reactant upon which the fused pyrimidine ring is to be formed doesnot contain a carboxamide group; that is, when --COR' is carboxy orcarbalkoxy, or haloformyl, reactant W-Z must provide the --NH group.

The favored process comprises using the appropriate2-amino-3-carboxamide (formula V wherein R'═NH₂) as reactant which iscondensed with the W-Z reactant to provide only the one-carbon fragmentto complete the pyrimidine ring.

Reaction of the 2-aminoquinoline-3-carboxylic acid derivative withreactant W-Z is carried out in a reaction-inert solvent and desirably,when W is --COR° or C(NH)--O--alkyl, one which will permit removal ofby-product alcohol and water by distillation. Representative solventsfor this cyclization are aromatic hydrocarbons such as xylene, toluene,benzene; an excess of the chosen diakyloxalate reactant; tetralin anddecalin.

Suitable solvents are readily determined by experimentation. A favoredsolvent when W-Z is a dialkyl oxalate is an excess of the dialkyloxalate because of its ability to solubilize the reactants and to permitsimple removal of by-product alcohol and water. Although the reactiontemperature is not critical, the reaction is generally run at anelevated temperature to facilitate removal of alcohol and water.Temperatures of from about 150° C. to about 185° C. are useful when adialkyl oxalate is used as solvent. Lower temperatures can be employedwith the more reactive oxalic acid derivatives (W-Z) such as ethyloxalylchloride. A final fusion or heating period is sometimes beneficialto achieving maximum cyclization and The 2-amino-3-cyano-4-substitutedquinoline thus produced is hydrolyzed to the corresponding4-substituted-2-aminoquinoline-3-carboxamide by heating with 95%sulfuric acid, followed by aqueous work-up. The process is thatdescribed by Campaigne et al., J. Hetero. Chem. 8, 111-120 (1971).

A further method comprises condensation of an appropriateo-nitrobenzaldehyde with a dialkylmalonate to produce an alkylα-carbalkoxy-β-(2-nitrophenyl)acrylate which is subsequently reduced tothe corresponding alkyl α-carbalkoxy-β-(2-aminophenyl)acrylate accordingto procedures described above. The reduced product spontaneouslycyclizes to an alkyl 2-oxo-quinoline-3-carboxylate. The 2-oxo derivativeis heated directly with 1-carbalkoxy formamidine in ethanol using sodiumethoxide to give compounds of formula I. Or, the 2-oxo derivative ischlorinated with a suitable chlorinating agent such as phosphoroustrichloride, phosphorous pentachloride, phosphorous oxychloride in areaction-inert solvent such as an aromatic hydrocarbon or a yield of thedesired pyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylic acid derivative.The addition of a small amount of a base, such as sodium hydride andalkali metal alkoxides, is frequently useful in promoting cyclization,expecially in making compounds of formula II.

When reactant W-Z results in production of the 2-cyano derivative ratherthan a 2-COR° derivative, the cyano group is converted to thecorresponding 2-carboxamide by acid hydrolysis. When W-Z is a monoacidhalide of a half-alkyl oxalic acid ester, an acid acceptor; i.e., anorganic or inorganic base, such as triethylamine, pyridine, sodiummethoxide, sodium hydroxide, is used to neutralize the by-product acidformed.

When reactant W-Z represents an alkyl ester of glycolic acid, the fusedpyrimidines of formulae I-III produced bear the hydroxymethyl group atthe 2-position. Such compounds serve as precursors for correspondingaldehydes. The conversion is accomplished by oxidation using chromicanhydride in pyridine (Sarett reagent) or chromicanhydride-pyridine-water (Cornforth reagent). The latter reagent ispreferred because of its ease of preparation and handling relative tothe Sarett reagent. Further oxidation of the 2-carboxaldehyde by, forexample, chromic anhydride-sulfuric acid at about 30° C-50° C. producesthe 2-carboxylic acid.

Alternatively, the appropriate alkyl benzyloxy acetate; e.g., ethylbenzyloxyacetate, is used as reagent W-Z to produce compounds offormulae I-III wherein the substituent is a 2-benzyloxymethyl group. Thebenzyl groups of the 2-benzyloxymethyl derivatives thus-produced areremoved by reaction with strong acids such as trifluoroacetic acid inthe manner described below.

The 5-substituted compounds of formula I are also prepared from theappropriate 4-substituted 2-aminoquinoline-3-carboxamide which, in turn,is prepared by the reaction of malononitrile with the appropriate R₁-(2-aminophenyl ketone, e.g., 2-aminobenzophenone (R₁ -phenyl) andaminoacetophenone (R₁ ═CH₃). halogenated aliphatic or aromatichydrocarbon (benzene, toluene, xylene, methylene chloride, ethylenechloride, chloroform, chlorobenzene) at a temperature of from about 50°C to 100° C.

The alkyl 2-chloroquinoline-3-carboxylate thus produced is reacted withan alkyl 1-guanylformate to provide the corresponding alkylpyrimido[4,5-b]quinolin-4(3H)-one-2carboxylate. This cyclization iscarried out according to known methods.

Still a further method comprises construction of the central pyridinering. It involves condensation of the appropriate o-nitrobenzaldehydewith an ester, e.g., an alkyl ester of4,6-dioxo(3H,5H)-tetrahydropyrimidine-2-carboxylic acid, in the presenceof a base to produce the corresponding 4,6-dioxo(3H,5H)-5-(2-nitrobenzylidene)tetrahydropyrimidine- 2-carboxylic acid esterwhich, upon subsequent reduction in the manner described above,spontaneously cyclizes to a compound of formula I. A variation on thismethod involves condensation of the o-nitrobenzaldehyde malondiamide,followed by reaction of the product with a dialkyl oxalate to form theabove nitrobenzylidene compound.

Compounds of formula II (R ═ COR°) are prepared by methods similar tothose described above for compounds of formula I but using, of course,in place of a 2-aminoquinoline-3-carboxamide, a2-aminonaphthalene-3-carboxamide. The reaction conditions for achievingconstruction of the pyrimidine ring are substantially the same as thosedescribed for compounds of formula I.

The compounds of formula III (R ═ COR°) are similarly prepared fromappropriate 2-aminoicotinamide or precursors thereto, e.g.,2-aminonicotinic acid, 2-nitropyridine-3-carboxamides or 3-carboxylicacids, 2-nitro- or 2-aminopyridine-3-carboxaldehydes. In preparingcompounds of formulae II and III, the favored routes comprise reactingW-Z with the appropriate 2-amino-3-carboxamide reactant.

The amide and hydroxamic acid derivatives of formula I, II, and III (R°═NH₂, NHOH) are prepared by methods described above from W-CONH₂,W-CONHOH or by reaction of the precursor alkyl ester of formulae I, II,and III with ammonia or hydroxylamine. The usual procedure whencomprises reacting the appropriate ester with ammonia or withhydroxylamine hydrochloride, usually in excess, in the presence of anacid acceptor such as triethylamine. The reaction is facilitated byheating under pressure, i.e., the reaction is carried out in a bomb, ina solvent such as ethanol for from about 4 to about 20 hours and theproduct then recovered by suitable means.

The 2-methyl and 2-ethyl analogs of formulae I and III are prepared bycyclization of the appropriate 2-amino-quinoline-3-carboxamide or2-aminonicotinamide with the appropriate alkanoic acid anhydride e.g.,acetic or propionic anhydride; or with triethyl orthoacetate or triethylorthoproionate in the presence of sulfuric acid. Treatment of theproduct with dilute alkali followed by reacidification provides the2-methyl or ethyl analogs. The preparation of2-methylpyrimido[4,5-b]-quinolin-4(3H)-one by this procedure is reportedby Taylor et al., J. Am. Chem. Soc. 78, 5108-15 (1956), as previouslynoted. The 2-ethyl analogs, new compounds, are primarily of value asintermediates for preparation of the corresponding 2-acetyl derivativesof formulae I and III.

The 2-acetyl derivatives of formulae I and III are prepared by oxidationof the corresponding 2-ethyl derivatives with selenium dioxide and waterin suitable solvent medium, for example, dioxane. In the usual procedurethe 2-ethyl derivative and selenium dioxide are used in about a 2:1molar ratio at an elevated temperature, e.g. from about 50° to about100° C. Additional selenium dioxide beyond the 2:1 molar ratio can beused to expedite the oxidation.

The 2-methyl analogs of formulae I and III are useful intermediates forpreparation of corresponding 2-carboxaldehydes and 2-carboxylic acids,and from them, of corresponding esters of the acids.

A useful procedure for preparing 2-carboxylic acids comprises refluxingthe appropriate 2-methyl derivative in a solvent such as ethanol with aslight excess of benzaldehyde in the presence of sodium ethoxide orpiperidine, or other base, to form the benzylidine adduct. The amount ofbase used is not critical but can vary from a catalytic amount (<1%) upto an equivalent amount. The benzylidene adduct is isolated by removalof the solvent and is then oxidized to the acid by excess cold potassiumpermanganate in aqueous acetone, or by ozonolysis. Alternatively, themethyl group is converted to the corresponding 2-bromomethyl compound byreaction with N-bromosuccinimide in chloroform. The succinimideby-product is removed by concentration of the reaction mixture andfiltration. The filtrate is taken to dryness and the residue dissolvedin aqueous sulfuric acid and treated with chromium trioxide to providethe acid.

Conversion of the 2-methyl groups to 2-carboxaldehyde groups is achievedby oxidation with selenium dioxide and water in the manner describedabove for conversion of 2-ethyl to 2-acetyl groups. Alternatively, the2-methyl group is transformed to the 2-bromomethyl group according tothe procedure mentioned above which is then hydrolyzed to thecorresponding 2-hydroxymethyl group.

The alkylene glycol esters of formula I-III (R═COR° wherein R° ishydroxyalkoxy) are conveniently prepared by a base catalyzedtransesterification process. The process comprises treating a compoundof formulae I-III wherein R° is alkoxy with an alkylene glycol,preferably in the presence of a catalytic amount of a base (i.e., fromabout 5% to about 20% by weight based upon the alkylene glycol used),such as triethylamine or calcium hydroxide, in air at a temperature offrom about 20° C. to about 50° C. Higher temperatures can be used butappear to offer no advantages.

Compounds of formula I wherein Y is other than hydrogen are prepared byalkylation of formula I compounds wherein Y is hydrogen. The procedurecomprises formation of the sodium salt by reaction of the appropriateformula I compound with sodium hydride in a suitable solvent, e.g.,N,N-dimethylformamide. Reaction of the sodium salt with I-Y, Br-Y (orCl-Y) affords the alkylated derivative. When using Cl-Y as alkylatingagent, the presence of a small amount of sodium or potassium iodide(from about 10% to 20% by weight of Cl-Y) serves to accelerate thereaction.

Compounds of formulae I-III wherein any of R₂, R₃, R₄, or R₅ is benzylmethylsulfinyl are readily prepared from the corresponding thioethercompounds by oxidation with an appropriate oxidizing agent such ashydrogen peroxide or a per acid such as m-chlorperbenzoic acid accord tomethods known to those skilled in the art.

The methylthio compounds are, in turn, readily prepared by the reactionof the corresponding chloro compound of formula IV; i.e., anα-cyano-β-(2-nitro-chlorophenyl)acrylamide, with sodium methylmercaptide. Modifications of this method are obvious to those skilled inthe art. For example, the methylthio ether of formula IV can be made byin situ formation of the methyl mercaptide salt. Similarly, benzyloxy,benzylthio, and alkoxy compounds are prepared by reacting thecorresponding chloro compound of formula IV with sodium benzyloxide,sodium benzylmercaptide, or a sodium alkoxide.

Compounds of formulae I-III wherein any of R₂ -R₅ is benzyloxy orbenzylthio serve as intermediates for the corresponding hydroxy andthiol compounds and acyl derivatives thereof. Debenzylation isconveniently accomplished by treating the benzyl ether or benzylthioether with trifluoroacetic acid. The debenzylated products are obtainedat their trifluoroacetate salts. The hydroxy and thiol compounds, inturn, are intermediates for preparation of corresponding alkanoyloxy,and benzoyloxy derivatives by acylation using the appropriate acidanhydride e.g. acetic anhydride. A catalytic amount of p-toluenesulfonicacid is generally used to expedite the reaction.

The products of this invention and the pharmaceutically-acceptablecationic salts thereof, are useful for the control (prophylactic andtherapeutic treatment) of allergic symptoms and reactions in mammals,and can be administered either as individual therapeutic agents or asmixtures of therapeutic agents, for example, with theophylline orsympathomimetic amines. They can be administered alone, but aregenerally administered with a pharmaceutical carrier selected on thebasis of the chosen route of administration and standard pharmaceuticalpractice. For example, they can be combined with variouspharmaceutically-acceptable inert carriers in the form of tablets,capsules, lozenges, troches, hard candies, powders, aerosol sprays,aqueous suspensions or solutions, injectable solutions, elixirs, syrupsand the like. Such carriers include solid diluents or fillers, sterileaqueous media and various non-toxic organic solvents. Moreover, the oralpharmaceutical compositions of this invention can be suitably sweetenedand flavored by means of various agents of the type commonly used forthis purpose.

The particular carrier selected and the proportion of active ingredientto carrier are influenced by the solubility and chemical nature of thetherapeutic compounds, the chosen route of administration and the needsof standard pharmaceutical practice. For example, when the compounds ofthis invention are administered orally in tablet form, excipients suchas lactose, sodium citrate, calcium carbonate and dicalcium phosphatecan be used. Various disintegrants such as starch, alginic acids andcertain complex silicates, together with lubricating agents such asmagnesium stearate, sodium lauryl sulphate and talc, can also be used inproducing tablets for the oral administration of these compounds. Fororal administration in capsule form, lactose and high molecular weightpolyethylene glycols are among the preferred materials for use aspharmaeutically-acceptable carriers. Where aqueous suspensions are to beused for oral administration, the compounds of this invention can becombined with emulsifying or suspending agents. Diluents such asethanol, propylene glycol, glycerine and chloroform and theircombinations can be employed as well as other materials.

For the purpose of parenteral administration and inhalation, solutionsor suspensions of these compounds in sesame or peanut oil or in aqueouspropylene glycol solutions can be employed, as well as sterile aqueoussolutions of the soluble pharmaceutically-acceptable salts describedherein. These particular solutions are especially suited forintramuscular and subcutaneous injection purposes should such method ofadministration be desired. The aqueous solutions, including those of thesalts dissolved in pure distilled water, are also useful for intravenousinjection purposes provided that their pH is properly adjustedbeforehand. Such solutions should also be suitably buffered, ifnecessary, and the liquid diluent first rendered isotonic with suffiientsaline or glucose.

The compounds can be administered to asthamatic subjects suffering frombronchoconstriction by means of inhalators or other devices which permitthe active compounds to come into direct contact with the constrictedareas of the tissues of the subject.

When administered by inhalation, the compositions can comprise (1) asolution or suspension of the active ingredient in a liquid medium ofthe type mentioned above for administratin via a nebulizer; (2) asuspension or solution of the active ingredient in a liquid propellantsuch as dichlorodifluoromethane or chlorotrifluoroethane foradministration from a pressurized container; or (3) a mixture of theactive ingredient and a solid diluent (e.g., lactose) for administrationfrom a powder inhalation device. Compositions suitable for inhalation bymeans of a conventional nebulizer will comprise about 0.1 to about 1% ofactive ingredient; and those for use in pressurized containers willcomprise from about 0.5 to about 2% of active ingredient. Compositionsfor use as powder inhalants can comprise ratios of active ingredient todiluent of from about 1:0.5 to about 1:1.5.

It is necessary that the active ingredient form a proportion of thecomposition such that a suitable dosage form will be obtained.Obviously, several dosage unit forms can be administered at about thesame time. Although compositions with less than 0.005% by weight ofactive ingredient might be used in certain instances, it is preferred touse compositions containing not less than 0.005% of the activeingredient; otherwise, the amount of carrier becomes excessively large.Activity increases with the concentration of the active ingredient. Thecomposition may contain 10, 50, 75, 95 or an even higher percentage byweight of the active ingredient.

The PCA reaction test procedure employed to evaluate the compounds ofthe present invention demonstrates an excellent correlation betweenactivity for compounds in this test and their utility in the treatmentof allergic asthma. The ability of agents to interfere with PCAreactions is measured in male Charles River Wistar rats, 170-210 g.Reaginic antisera is prepared according to Mota, Immunology, 7, 681(1964) using hen egg albumin and B. pertussis. Hyperimmune antisera tohen egg albumin is prepared according to Orange, et al., J. Exptl. Med.,127, 767 (1968). Forty-eight hours prior to antigen challenge thereaginic antisera is injected intradermally (i.d.) into the shaved skinof a normal rat's back; five hours before challenge the hyperimmuneantisera is similarly injected; five hours later, at a third site, 60mcg. histamine dihydrochloride is injected i.d. as a check forantihistaminic and unspecific types of blockage; the compounds of theinstant invention or saline are then administered i.v. and immediatelyfollowed by 2.5 mg. Evan's blue dye and 5 mg. egg albumin in saline. Inthe case of oral administration Evan's blue dye and egg albumen aregiven five minutes after administration of the drug. Thirty minuteslater the animals are asphyxiated using chloroform and the skin of theback removed and reversed for observation. A score is assigned eachinjection site equal to the product of the diameter of the site in mm.and a grade of 0.1, 0.5, 1, 2, 3 or 4 proportional to intensity of dyecoloration. The scores for a given injection site are summed for eachgroup of 8 animals and compared to the saline treated controls. Thedifference is expressed as percent blockade due to the compound employed

Compounds representative of those in the present invention are tested bythe aforementioned procedure, and the resulting activities are reportedas the degree (%) of protection. Disodium cromoglycate, a commerialantiallergy agent, is included for comparison. ##STR3##

                                      TABLE I.                                    __________________________________________________________________________    Antiallergy Activity of Pyrimido[4,5-b]                                       Quinoline-4(3H)-One-2-Carboxylic Acid                                         Derivatives (Formula I)                                                                                        I.V.*     Oral                               R        R.sub.1                                                                          R.sub.2                                                                           R.sub.3                                                                             R.sub.4                                                                              R.sub.5                                                                           mg/kg                                                                              %    mg/kg                                                                              %                             __________________________________________________________________________    COOC.sub.2 H.sub.5                                                                     H  H   H     H      H   10   100  100  80                                                             3    99   60   100.sup.3                                                      1    100.sup.4                                                                          30   72.sup.3                                                       0.3  82.sup.6                                                                           10   775.sup.3                                                      0.1  45.sup.6                                                                           3    69.sup.2                                                       0.03 30.sup.6                                                                           1    12.sup.2                      COONa    H  H   H     H      H   1    92   100  96                                                             0.3  68   30   57                                                                       10   0                             COO(n-C.sub.4 H.sub.9)                                                                 H  H   H     H      H   1    90   30   50                                                             0.03 6                                       CONH.sub.2                                                                             H  H   H     H      H   3    98   60   23                            COOC.sub.2 H.sub.5                                                                     H  H   OCH.sub.3                                                                           OCH.sub.3                                                                            H   1    100  10   80.sup.17                                                      0.3  90.sup.3                                                                           3    75.sup.22                                                      0.1  90.sup.12                                                                          1    51.sup.26                                                      0.03 75.sup.14                                                                          0.03 30.sup.20                                                      0.01 70.sup.17                                                                0.003                                                                              36.sup.14                               COO(n-C.sub.4 H.sub.9)                                                                 H  H   OCH.sub.3                                                                           OCH.sub.3                                                                            H   3    90   30   81                                                             0.3  94                                                                       0.03 100                                                                      0.003                                                                              64                                      COOCH.sub.2 CH.sub.2 OH                                                                H  H   OCH.sub.3                                                                           OCH.sub.3                                                                            H   3    97   10   65                                                             0.3  94                                                                       0.03 92                                      CONH.sub.2                                                                             H  H   OCH.sub.3                                                                           OCH.sub.3                                                                            H   3    87   30   4                             CONHOH   H  H   OCH.sub.3                                                                           OCH.sub.3                                                                            H   3    92   60   3                             COONa    H  H   OCH.sub.3                                                                           OCH.sub.3                                                                            H   0.1  100  10   17.sup.2                                                       0.03 96                                                                       0.01 71                                      CH.sub.3 H  H   OCH.sub.3                                                                           OCH.sub.3                                                                            H   3    77.sup.4                                                                           3    67.sup.6                                                       0.3  45.sup.4                                                                           1    43.sup.6                                                       0.03 11.sup.4                                C.sub.2 H.sub.5                                                                        H  H   OCH.sub.3                                                                           OCH.sub.3                                                                            H   3    56   60   0                             COCH.sub.3                                                                             H  H   OCH.sub.3                                                                           OCH.sub.3                                                                            H   3    100  10   15                                                             1    21                                                                       0.1  19.sup.2                                COOC.sub.2 H.sub.5                                                                     H  H   OCH.sub.3                                                                           OC.sub.2 H.sub.5                                                                     H   3    97   30   80.sup.4                                                       0.3  94.sup.2                                                                           10   73.sup.7                                                       0.1  94.sup.2                                                                           3    52.sup.6                                                       0.03 85.sup.4                                                                           1    44.sup.7                                                       0.01 57.sup.3                                                                           0.3  31.sup.2                                                       0.003                                                                              66.sup.3                                COOC.sub.2 H.sub.5                                                                     H  H   --O--CH.sub.2 --O--                                                                        H   1    70   30   0                                                              0.1  0                                       COOC.sub.2 H.sub.5                                                                     H  H   --O--CH.sub.2 CH.sub.2 --O--                                                               H   3    72                                                                       1    64                                      COOC.sub.2 H.sub.5                                                                     H  H   OC.sub.2 H.sub.5                                                                     OC.sub.2 H.sub.5                                                                    H   3    100  10   81.sup.3                                                       0.1  90.sup.2                                                                           3    64.sup.6                                                       0.03 60.sup.3                                                                           1    40.sup.6                                                       0.01 43.sup.3                                                                           0.3  42.sup.4                                                       0.003                                                                              21.sup.3                                COOC.sub.2 H.sub.5                                                                     H  H   OC.sub.2 H.sub.5                                                                    OCH.sub.3                                                                            H   3    100  10   92.sup.4                                                       0.1  99.sup.2                                                                           3    83.sup.6                                                       0.03 85.sup.4                                                                           1    76.sup.7                                                       0.01 72.sup.4                                                                           0.3  56.sup.5                                                       0.003                                                                              50.sup.4                                COOC.sub.2 H.sub.5                                                                     H  H   OC.sub.2 H.sub.5                                                                    O-(n-C.sub.4 H.sub.9)                                                                H   3    90   10   67.sup.3                                                       1    95   3    43.sup.2                                                       0.3  44.sup.3                                                                           1    3.sup.2                                                        0.1  28                                                                       0.03 0                                       COOC.sub.2 H.sub.5                                                                     H  H   OC.sub.2 H.sub.5                                                                    OC.sub.7 H.sub.7                                                                     H   3    71.sup.4                                                                           30   0                                                              0.3  30.sup.2                                                                           10   0                                                              0.1  3.sup.2                                 COOC.sub.2 H.sub.5                                                                     H  H   H     OCH.sub.3                                                                            OCH.sub.3                                                                         3    100  60   26                                                             0.3  39   10   0                             COOC.sub.2 H.sub.5                                                                     H  H   OCH.sub.3                                                                           H      H   3    100  10   43                                                             0.3  87   3    32                                                             0.1  68.sup.2                                COOC.sub.2 H.sub.5                                                                     H  H   H     OCH.sub.3                                                                            H   3    90   10   43                                                             0.3  20                                                                       0.03 0                                       COOC.sub.2 H.sub.5                                                                     H  OCH.sub.3                                                                         H     H      OCH.sub.3                                                                         3    100  30   23                                                             0.3  25                                                                       0.03 0                                       COOC.sub.2 H.sub.5                                                                     H  H   OCH.sub.3                                                                           H      OCH.sub.3                                                                         3    97   30   41                                                             0.3  38                                                                       0.03 14                                      COOC.sub.2 H.sub.5                                                                     H  H   SCH.sub.3                                                                           H      H   3    88   30   100                                                            0.3  91   10   66                                                             0.03 8    3    21                                                                       1    0                             COOC.sub.2 H.sub.5                                                                     H  H   SOCH.sub.3                                                                          H      H   3    100  30   12                                                             0.3  58                                                                       0.03 0                                       COOC.sub.2 H.sub.5                                                                     H  H   OCH.sub.3                                                                           OCH.sub.3                                                                            OCH.sub.3                                                                         3    88   10   0                                                              0.3  23                                                                       0.03 33                                      COOC.sub.2 H.sub.5                                                                     H  H   H     F      H   0.1  2                                       COOC.sub.2 H.sub.5                                                                     H  H   F     H      H   3    82   30   17                                                             1    90                                                                       0.03 0                                       COOC.sub.2 H.sub.5                                                                     H  H   Cl    H      H   1    70                                                                       0.03 0                                       COOC.sub.2 H.sub.5                                                                     H  Cl  H     H      H   1    96   30   57                                                             0.03 11                                      COOC.sub.2 H.sub.5                                                                     C.sub.6 H.sub.5                                                                  H   H     H      H   3    100  10   0                                                              1    95   1    0                                                              0.3  51                                                                       0.1  9                                       COOC.sub.2 H.sub.5                                                                     H  H   CH.sub.3 COO                                                                        OCH.sub.3                                                                            H   3    100  10   40                                                             .003 53                                      COOC.sub.2 H.sub.5                                                                     H  H   OH    OCH.sub.3                                                                            H   0.03 97   30   6                                                              0.01 98                                                                       0.003                                                                              94                                                                       0.0003                                                                             38                                      COOH     H  H   OH    OCH.sub.3                                                                            H   3    100                                                                      0.01 86                                                                       .003 90                                      COO-(n-C.sub.4 H.sub.9)                                                                H  H   OH    OCH.sub.3                                                                            H   3    100  10   67.sup.2                                                       .003 52                                      COO-(n-C.sub.4 H.sub.9)                                                                H  H   OC.sub.7 H.sub.7                                                                    OCH.sub.3                                                                            H   3    100  10   12                                                             .03  57                                      COO-(n-C.sub.4 H.sub.9)                                                                H  H   CH.sub.3 COO                                                                        OCH.sub.3                                                                            H   3    100  10   36                            COOC.sub.2 H.sub.5                                                                     H  H   OCH.sub.3                                                                           OC.sub.7 H.sub.7                                                                     H   3    94                                                                       0.3  23                                      COOC.sub.2 H.sub.5                                                                     H  H   OC.sub.7 H.sub.7                                                                    H      H   3    85   10   60                                                             0.3  23   3    3                             COOC.sub.2 H.sub.5                                                                     H  H   OH    H      H   0.3  92   10   13                                                             0.03 21   3    4                             COOH     H  H   OH    H      H   3    100                                                                      0.03 91                                                                       .003 4                                       COOC.sub.2 H.sub.5                                                                     H  H   OCH.sub.3                                                                           OH     H   0.003                                                                              0                                                                        0.3  100                                                                      3.0  100                                              Disodium                100  100  100  0                                      chromoglycate           30   99.sup.2                                                                 10   89.sup. 3                                                                3    78                                                                       1    56.sup.8                                                                 0.3  29.sup.5                                                                 0.1  19.sup.3                                __________________________________________________________________________     *The superscripts indicate a particular value is an average of two or mor     determinations.                                                          

                  TABLE II.                                                       ______________________________________                                        Antiallergy Activity of Benzo[g]Quinazolin-                                   4(3H)-One-2-Carboxylic Acid Derivatives                                       (Formula II)                                                                   ##STR4##                                                                                    I.V.      Oral                                                 R°                                                                              R.sub.2                                                                             R.sub.3                                                                             R.sub.4                                                                           R.sub.5                                                                           mg./kg.                                                                              %    mg./kg.                                                                              %                             ______________________________________                                        COOC.sub.2 H.sub.5                                                                     H     H     H   H   10     27   100    38                            COOH*    H     H     H   H   10     100  100    9                                                          3      36   30     0                                                          1      14   10     33                            ______________________________________                                         *Tested as disodium salt.                                                

                  TABLE III.                                                      ______________________________________                                        Antiallergy Activity of Pyrido[2,3-d]-                                        Pyrimidin-4(3H)-One-2-Carboxylic Acid                                         Derivatives (Formula III)                                                      ##STR5##                                                                                   I.V.      Oral                                                  R°                                                                            R.sub.2                                                                              R.sub.3                                                                              R.sub.4                                                                            mg./kg.                                                                              %    mg./kg. %                               ______________________________________                                        OC.sub.2 H.sub.5                                                                     H      H      H    10     95   100     0                               ______________________________________                                    

as regards the dosage regimen of the compounds of this invention, thephysician will ultimately determine the dosage which will be mostsuitable for a particular individual, and it will vary with age, weightand response of the particular patient as well as with the nature andextent of the symptoms, the pharmacodynamic characteristics of theparticular agent to be administered, and the route of administrationchosen. Generally, small doses will be administered initially, with agradual increase in the dosage until the optimum level is determined. Itwill often be found that when the composition is administered orally,larger quantities of the active ingredient will be required to producethe same level as produced by a small quantity administeredparenterally.

Having full regard for the foregoing factors, it is considered that aneffective daily oral dosage of the compounds of the present invention inhumans of from about 10 to about 1500 mg. per day, with a preferredrange of about 10 to about 600 mg. per day in single or divided doses,or at about 0.2 to about 12 mg./kg. of body weight will effectivelyalleviate bronchoconstriction in human subjects. These values areillustrative and there may, of course, be individual cases where higheror lower dose ranges are merited.

When administered intravenously or by inhalation, the effective dailydose is from about 0.5 to about 400 mg. per day, and preferably fromabout 0.25 to 200 mg. per day, or at about 0.005 to 4 mg./kg. of bodyweight in single or divided doses.

Ethyl 7,8-dimethoxypyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate isactive via the oral, intravenous, intraperitoneal and inhalation routesof administration. It is active intraperitoneally at 0.3-1 mg./kg.; andorally in the range of 0.3-30 mg./kg. When administered by aerosol,concentration related responses are observed using 0.3-30 mg./ml.solutions. Intravenously, it is active at a level as low as 0.003mg./kg.

It has been observed that ethyl7,8-dimethoxypyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate causes amarked but transient hypotension and bradycardia in dogs. The effectappears to be species specific. It appears to be relatively free oftoxicity since intravenous doses of 1000 mg./kg. did not cause death inmice.

In addition to compounds of formula I above, analogs thereof wherein R₁is substituted phenyl wherein the substituent is at least one of alkyl,alkoxy, alkylenedioxy and halo, and compounds of formulae I, II and IIIdescribed herein, and analogs thereof wherein COR° is an amide derivedfrom an amino acid, e.g., ethyl glycine, and those wherein COR° isreplaced by a methyl or a 5-tetrazolyl group are useful antiallergyagents in the same manner as are compounds of formulae I-III. So alsoare analogs of formulae I, II and III, and the just described analogsthereof wherein -COR° is replaced by methyl or a 5-tetrazolyl group, butin which the 4-keto group is replaced by thiono (═S).

Compounds wherein the substituent at the 4-position is thiono (═S)rather than keto (═O) are prepared in the same manner as are the ketocompounds but using the appropriate cyanothionoacetic acid reactantCN-CH₂ -CSR' in place of the cyanoacetic acid reactant in either ofroutes A and B above. Alternatively, the appropriate2-aminonicotinonitrile, 2-aminoquinolino-3-carbonitrile or2-aminonaphthalene-3-carbonitrile is reacted with concentrated ammoniumhydroxide at about 40°-80° C. while bubbling hydrogen sulfide throughthe solution for several hours, e.g., 3-5 hours; or by reacting theappropriate nitrile in pyridine containing triethylamine while bubblinghydrogen sulfide through the solution at ambient temperature. Suchprocedures are described by Mautner, J. Org. Chem. 23, 1450 (1958) andBercat-Vatterone, Annales de Chimie 7, 312 (1962), respectively. Thethioamides thus obtained are reacted with various oxalate derivativesY-Z as described above for Routes A and B.

The tetrazolyl substituent (T) at the 2-position is prepared from thecorresponding compound wherein the 2-substituent is cyano. The reactioncomprises treating the 2-cyano compound with hydrazoic acid or,preferably, a mixture of sodium azide and ammonium chloride inN,N-dimethylformamide or dimethylsulfoxide at from about 100° C. to thereflux temperature of the mixture for from about 5 to about 24 hours.The addition of a small excess (1-5%) of ammonium azide or of a Lewisacid serves to expedite the reaction. Alternatively, a mixture of sodiumazide and acetic acid can be used to generate the hydrazoic acid insitu. With this system as source of hydrazoic acid, refluxing n-butanolserves as a useful solvent and the reaction mixture is heated to refluxfor about 3 to 5 days.

The required 2-cyano derivatives are obtained by reacting theappropriate 3-amino-2-naphthoic acid, 2-aminonicotinic acid or2-aminoquinolin 3-carboxylic acid with cyanogen, as described by Griess,Ber. 2, 415 (1869) and Ber. 11, 1985 (1878). Alternatively, andpreferably, the 2-cyano compounds are prepared by dehydration of thecorresponding 2-carboxamides with, for example, phosphoryl chlorideaccording to the procedure set forth in Org. Syn. Coll. Vol. 3, 535(1955), or with phosphorous pentoxide as described by Hayoshi et al.,Chem. Pharm. Bull. (Japan) 12, 43 (1964). Still further, the dehydrationcan be accomplished by means of p-toluenesulfonyl chloride (tosylchloride) and pyridine according to the procedure of Stephens et al., J.Am. Chem. Soc. 77, 1701 (1955).

Additionally, 2-tetrazole derivatives of formulae I, II and III areprepared by converting the 2-carboxamide derivatives thereof to thecorresponding-2-(N-p-methoxybenzyl)carboxamide according to knownmethods. The N-substituted amide is reacted with phosgene in pyridinefor from about 2 to 5 hours to give an iminochloride. The iminochlorideis treated with sodium azide in dry N,N-dimethylformamide at ambienttemperature for from 2 to 4 hours to provide the 1,5-disubstitutedtetrazole. The p-methoxybenzyl group is then removed by treating thesubstituted tetrazole with trifluoroacetic acid at about 40° C. and anequivalent of anisole. (The 4-oxo group, if converted to a 4-chlorogroup by phosgene, is regenerated by alkaline hydrolysis according tostandard procedures.)

In still a further method, the 2-(5-tetrazolyl) derivatives are preparedby heating 5-carbethoxytetrazole (Oliveri-Mandola, Gazz. Chim. Ital. 41,I, 59 (1911)) with the appropriate 2-aminoquinolin-3-carboxamide, the3-aminonaphthalene-2-carboxamide or the 2-aminonicotinamide reactant inan inert solvent. This procedure corresponds to the common step ofRoutes A and B above but wherein the Y-Z reactant is5-carbethoxytetrazole.

The amino acid derived amides are conveniently obtained from thecorresponding lower alkyl ester, e.g., ethyl ester, by reaction with theappropriate amino acid or derivative thereof in the manner described inExamples VII and IX below. The compound of formula I, N-carbethoxymethyl7,8-dimethoxypyrimido-[4,5-b]quinolin-4(3H)-one-2-carboxamide (R₁, R₂,R₅ ═ H; R₃, R₄ ═ OCH₃ ; R° = NHCH₂ COOC₂ H₅), when administeredintravenously at 30 and 3 mg./kg. of body weight to rats affords 96 and32% protection, respectively in the PCA test.

EXAMPLE I Ethyl Pyrimido[4,5-b]Quinolin-4(3H)-One-2-Carboxylate

A. 2-aminoquinoline-3-Carboxamide

Cyanoacetamide (19.4 g., 0.23 mole) is added to a solution of sodiumethoxide (6.65 g., 0.29 mole) in absolute ethanol (460 ml.) maintainedat 50° C. The mixture is stirred and o-aminobenzaldehyde (28.0 g., 0.23mole) in absolute ethanol (100 ml.) added. After fifteen minutesstirring at 50° C., the reaction mixture is cooled in an ice bath,filtered and dried to give 34.5 g. (84% yield) of product; m.p.240°-242° C.

b. ethyl Pyrimido [4,5-b]quinoline-4(3H)-one-2-carboxylate

A mixture of 2-aminoquinoline-3-carboxamide (25.0 g., 0.134 mole) anddiethyl oxalate (500 ml.) is heated to reflux for 4 hours whiledistilling off the ethanol-water formed. The reaction mixture is thencooled to room temperature, the solid product filtered off, washed withdiethyl oxalate and air dried to give 22.6 g. of brownish-green solid;m.p. 245°-246° C. It is purified by recrystallization, withdecolorization, from hot chloroform. The off-white solid thus obtained(16.2 g., 45% yield) melts at 247°-248° C.

Analysis: Calcd. for C₁₄ H₁₁ N₃ O₃ : C, 62.51; H, 4.24; N, 15.67% Found:C, 62.44; H, 4.24; N, 15.67%.

The same compound is obtained by: (a) refluxing equimolar amounts of1-carbethoxyformimidate and ethyl 2-aminoquinoline-3-carboxylate inethanol for three hours. The reaction mixture is concentrated, theproduct collected by filtration and recrystallized from hot chloroform;or (b) refluxing equimolar amounts of 1-carbethoxyformamidine and2-aminoquinoline-3-carboxamide in ethanol for 3-4 hours in the presenceof an equimolar amount of sodium ethoxide. The reaction mixture isworked up as described in (a) above.

EXAMPLE II Ethyl 7,8-Dimethoxypyrimido[4,5-b]Quinolin-4(3H)-One-2-Carboxylate

A. α-cyano-β-(2-Nitro-4,5-Dimethoxyphenyl)Acrylamide

Piperidine (2.1 g., 0.0237mole) and 2-cyanoacetamide (22.0g., 0.263mole) are added to a slurry of 6-nitroveratraldehyde (50.0 g., 0.237mole) in methanol (500 ml.). The mixture is heated to reflux for twohours, and then cooled in an ice bath and filtered. The bright yellowfilter cake is washed with cold isopropanol (300 ml.) and then airdried. Yield = 60.1 g. (93%); m.p. 265°-266° C.

Analysis: Calcd. for C₁₂ H₁₁ N₅ O₃ : C, 51.99; H, 4.00, N, 15.16%; C,51.96; H, 4.20; N, 15.23%.

Following the procedure of preparations above, but using the appropriatealkoxy substituted nitrobenzaldehyde reactant, the compounds listedbelow are prepared:

    ______________________________________                                         ##STR6##                                                                     R.sub.2                                                                             R.sub.3 R.sub.4   R.sub.5                                                                             m.p. (° C)                                                                       % Yield                               ______________________________________                                        H     OCH.sub.3                                                                             H         OCH.sub.3                                                                           231-2 (dec.)                                                                            20.sup.(a)                            OCH.sub.3                                                                           H       H         OCH.sub.3                                                                           247-8 (dec.)                                                                            82.5                                  H     H       OCH.sub.3 H     157-2 (dec.)                                                                            42                                    H     OCH.sub.3                                                                             OCH.sub.3 OCH.sub.3                                                                           244.5 (dec.)                                                                            73.5                                  H     OC.sub.2 H.sub.5                                                                      O-n-C.sub.4 H.sub.9                                                                     H               54                                    H     OC.sub.2 H.sub.5                                                                      OC.sub.7 H.sub.7                                                                        H     167-167.5 (dec.)                                                                        73                                    H     OC.sub.2 H.sub.5                                                                      OCH.sub.3 H     243-4 (dec.)                                                                            62                                    H     OC.sub.2 H.sub.5                                                                      OC.sub.2 H.sub.5                                                                        H     191-3 (dec.)                                                                            79                                    H     OCH.sub.2CH.sub.2 O                                                                         H       301.5 (dec.)                                                                            98.2                                    H     OC.sub.7 H.sub.7                                                                      OCH.sub.3 H     157-8     45                                    H     OCH.sub.3                                                                             OC.sub.7 H.sub.7                                                                        H     182-3     52                                    H     OC.sub.7 H.sub.7                                                                      H         H     125-6     47                                    ______________________________________                                    

b. 6,7-dimethoxy-2-Aminoquinoline-3-Carboxamide

Iron powder (65.2 g., 1.22 moles) is added over a period of one-halfhour to a slurry of α-cyano-β-(2-nitro-4,5-dimethoxyphenyl)acrylamide(75.0g., 0.271 mole) in a 50% solution of aceticacid-N,N-dimethylformamide (750 ml.) at 75° C. When addition of the ironpowder is complete, the mixture is heated to 90° C. for four hours andthen filtered while hot. The filter cake is washed with hot acetic acid(150 ml.). The dark red filtrate is gradually added to IN hydrochloricacid (1500 ml.) and the pink precipitate recovered by filtration andrecrystallized from an excess (10%) of aqueous sodium hydroxide. Thesolid is filtered, washed with cold isopropanol and dried to give thetitle product as yellow crystals. Yield ═ 57.1 g. (83.5 %); mpp.274-275° C.

Analysis: Calcd. for C₁₂ H₁₅ N₃ O₃ : C, 58.30; H, 5.29; N, 16.99%.Found: C, 58.06; H, 5.29; N, 17.25%.

Upon repetition of procedure B above but using the appropriateα-cyano-β-(2-nitro-alkoxyphenyl)acrylamide from procedure A, thefollowing compounds are prepared:

    ______________________________________                                         ##STR7##                                                                     R.sub.2                                                                             R.sub.3 R.sub.4   R.sub.5                                                                             m.p. (° C.)                                                                      % Yield                               ______________________________________                                        H     OCH.sub.3                                                                             H         OCH.sub.3                                                                           284-286   52                                    OCH.sub.3                                                                           H       H         OCH.sub.3                                                                           263-4(dec)                                                                              78.5                                  H     H       OCH.sub.3 H     281-2(dec)                                                                              82                                    H     OCH.sub.3                                                                             OCH.sub.3 OCH.sub.3                                                                           240-1.5(dec)                                                                            83.2                                  H     OC.sub.2 H.sub.5                                                                      O-n-C.sub.4 H.sub.9                                                                     H     252       85                                    H     OC.sub.2 H.sub.5                                                                      OC.sub.7 H.sub.7                                                                        H     279-80(dec)                                                                             73                                    H     OC.sub.2 H.sub.5                                                                      OCH.sub.3 H     234-5(dec)                                                                              83.7                                  H     OC.sub.2 H.sub.5                                                                      OC.sub.2 H.sub.5                                                                        H     243-4(ded)                                                                              90.8                                  H     OCH.sub.2 CH.sub.2 O                                                                        H       269.5(dec)                                                                              26.5                                    H     OC.sub.7 H.sub.7                                                                      OCH.sub.3 H     264-6     80                                    H     OCH.sub.3                                                                             OC.sub.7 H.sub.7                                                                        H     282-3(dec)                                                                              95                                    H     OC.sub.7 H.sub.7                                                                      H         H     238-9     94                                    ______________________________________                                    

c. ethyl 7,8-dimethoxypyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate

To a round-bottomed flask equipped with stirrer, reflux condenser andDean-Stark apparatus and containing a mixture of diethyl oxalate (50ml.) and xylene (80 ml.) at reflux is added6,7-dimethoxy-2-aminoquinoline-3-carboxamide (3.0 g., 0.012 mole). Thexylene, water and ethanol are distilled off and collected over a fourhour period. When all the xylene is removed, the reaction mixture isbrought to 185° C., cooled to about 100° C. and then slowly poured intochloroform (300 ml.). The chloroform solution is cooled and the brownprecipitate which forms removed by filtration. The filtrate isdecolorized with charcoal, concentrated and chilled to give acrystalline mass. The crystals are taken up in hot chloroform, thesolution charcoalled, filtered and concentrated to give pale yellowcrystals; 0.59 g. (15%); m.p. 273°-273° C. (dec.)

Analysis: Calcd. for C₁₆ H₁₅ N₃ O C, 58.41; H, 4.60; N, 12.77%. Found:C, 57.91; H, 4.53; N, 12.37%.

An alternative route to this product comprises heating a mixture ofethyl 6,7-dimethoxy-2-aminoquinoline-3-carboxylate (1.38 g., 5.0 mM),ethyl 1-carbethoxyformimidate hydrochloride (1.82 g., 10 mM),triethylamine (5.1 g., 5.0 mM), ethanol (50 ml.) andN,N-dimethylformamide (20 ml.) on a steam bath for 17 hours. Thereaction mixture is cooled and the solid which separates filtered off,triturated with hot chloroform and then recrystallized from chloroformto give 0.170 g. of product. M.P. 273°-274° C. (dec.)

A further alternative route is as follows:

To ethyl oxalyl chloride (80.0 ml.) is added6,7-dimethoxy-2-aminoquinoline-3-carboxamide (2.0 g., 0.81 mM) and themixture heated at 95° C. for two days. The reaction mixture is thencooled and filtered. The solid product is triturated with andrecrystallized from hot chloroform.

Still further, a mixture of 6,7-dimethoxy-2-aminoquinoline-3-carboxamide(0.5 g., 2 millimoles), ethyl cyanoformate (0.43 g., 44 millimiles) andbenzene (30 ml.) is refluxed for three days. The mixture is then cooled,filtered and the solid extracted with chloroform. Concentration of thechloroform extract affords the product which is recrystallized fromchloroform.

Following the first procedure of C above, but using the appropriatealkoxy substituted 2-aminoquinoline-3-carboxamide reactant from B aboveand the appropriate ester of oxalic acid, the compounds listed below areprepared:

    __________________________________________________________________________     ##STR8##                                                                     R°                                                                           R.sub.2                                                                           R.sub.3                                                                           R.sub.4                                                                             R.sub.5                                                                           m.p. (° C)                                                                    % Yield                                        __________________________________________________________________________    O-n-C.sub.4 H.sub.9                                                                 H   OCH.sub.3                                                                         OCH.sub.3                                                                           H   263-4(dec)                                                                           14.5                                           OC.sub.2 H.sub.5                                                                    H   OCH.sub.3                                                                         H     OCH.sub.3                                                                         256-7(dec)                                                                           35                                             OC.sub.2 H.sub.5                                                                    OCH.sub.3                                                                         H   H     OCH.sub.3                                                                         254-5(dec)                                                                           24                                             OC.sub.2 H.sub.5                                                                    H   H   OCH.sub.3                                                                           H   263-4(dec)                                                                           9                                              OC.sub.2 H.sub.5                                                                    H   OCH.sub.3                                                                         OCH.sub.3                                                                           OCH.sub.3                                                                         250(dec)                                                                             31.4                                           OC.sub.2 H.sub.5                                                                    H   OC.sub.2 H.sub.5                                                                  O-n-C.sub.4 H.sub.9                                                                 H   201-3(dec)                                                                           16                                             OC.sub.2 H.sub.5                                                                    H   OC.sub.2 H.sub.5                                                                  OC.sub.7 H.sub.7                                                                    H   241-2(dec)                                                                           41                                             OC.sub.2 H.sub.5                                                                    H   OC.sub.2 H.sub.5                                                                  OCH.sub.3                                                                           H   264-5(dec)                                                                           16                                             OC.sub.2 H.sub.5                                                                    H   OC.sub.2 H.sub.5                                                                  OC.sub.2 H.sub.5                                                                    H   243-4(dec)                                                                           19.1                                           OC.sub.2 H.sub.5                                                                    H   OCH.sub.2 CH.sub.2 O                                                                    H   252.5(dec)                                                                           11.2                                           OC.sub.2 H.sub.5                                                                    H   OC.sub.7 H.sub.7                                                                  OCH.sub.3                                                                           H   274-5  25                                             OC.sub.2 H.sub.5                                                                    H   OCH.sub.3                                                                         OC.sub.7 H.sub.7                                                                    H   254-5(dec)                                                                           8                                              O-n-C.sub.4 H.sub.9                                                                 H   OC.sub.7 H.sub.7                                                                  OCH.sub.3                                                                           H   261-2(dec)                                                                           13                                             OC.sub.2 H.sub.5                                                                    H   OC.sub.7 H.sub.7                                                                  H     H   256-7(dec)                                                                           32                                             __________________________________________________________________________

D. 7,8-dimethoxypyrimido[4,5-b]Quinolin-4(3H)-One-2-Carboxylic Acid

Ethyl 7,8-dimethoxypyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate (250mg., 7.4 mM) in 5% aqueous sodium hydroxide (37.5 ml.) is stirred atroom temperature for twenty hours. The ester dissolves within tenminutes and is followed by the gradual appearance of a light coloredprecipitate. The reaction mixture is acidified by the slow addition of10% aqueous hydrochloric acid (13 ml.). The light colored precipitatedissolves and a yellow precipitate forms. The acid mixture is stirredfor 45 minutes and then filtered. The filter cake is washed with waterand then dried in vacuo. Yield = 140 mg. (63%) of yellow solid. M.P.277°-280° C. (dec.). Analysis shows it to be 86% pure. The remainder issodium chloride plus a small amount of water. It is purified byrecrystallization from trifluoroacetic acid. The trifluoroacetate saltmonohydrate thus obtained melts at 281°-283° C. (dec.).

Analysis: Calcd. for C₁₄ H₁₁ O₅ N₃. CF₃ COOH-H₂ O: Calcd. C; 44.34; H,3.25; N, 9.69; F, 13.15% Found: C, 43.95; H, 3.17; N, 9.99; F, 13.75%

Ethyl-7-methoxy-8-ethoxypyrimido[4,5-b]quinoline-4(3H)-one-2-carboxylateis similarly prepared according to procedures A-C, beginning with3-methoxy-4-ethoxy-6-nitrobenzaldehyde. It melts at 264°-265° C. (dec.)

It and the remaining products of Example II-C are hydrolyzed accordingto procedure D to afford the corresponding acids.

EXAMPLE III Ethyl7-Fluoropyrimido[4,5-b]-Quinolin-4(3H)-One-2-Carboxylate

A. α-cyano-β-(2-Nitro-5-Fluorophenyl)Acrylamide

A mixture of 3-fluoro-6-nitrobenzaldehyde (10.0 g., 0.0592 mole),2-cyanoacetamide (5.24 g., 0.0622 mole), piperidine (0.37 g., 4.36millimole) and ethanol (92 ml.) is heated to reflux on a steam bath fortwo hours. It is then cooled in an ice-bath whereupon the productprecipitates and is recovered by filtration, washed with cold ethanoland dried. Yield = 9.1 g. (65%) of crude product. M.P. 162°-166° C.

It is of sufficient purity for use in the succeeding step.

B. 6-fluoro-2Aminoquinoline-3-Carboxamide

Iron powder (8.52 g., 0.152 mole) is gradually added over a forty minuteperiod to a slurry of α-cyano-β-(2-nitro-5-fluorophenyl)acrylamide (7.97g., 0.034 mole) in acetic acid (100 ml.) at 85° C. When addition of theiron powder is complete, the mixture is heated to 95°-100° C. for 1.5hours and then filtered hot through diatomaceous earth. The filtrate iscooled in an ice bath and then filtered to give a tan crystalline solid.The solid is partitioned between ethyl acetate and water, the organicphase separated, dried over anhydrous sodium sulfate and concentrated toyield 6.34 g. (90%) of the title amide as yellow crystals. M.P.232°-236° C.

c. ethyl 7-fluoropyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate

A mixture of diethyl oxalate (57.2 g., 0.392 mole) and6-fluoro-2-aminoquinoline-3-carboxamide (5.34 g., 0.0261 mole) is heatedfor eighteen hours at 160° C. under a nitrogen atmosphere and thenallowed to cool to room temperature. Hexane (300 ml.) is added, themixture stirred and filtered to provide the desired product. It iswashed with hexane and dried. Yield = 4.9 g. (71%); m.p. 272° C. (dec.).

Analysis: Calcd. for C₁₉ H₁₀ FN₃ O₃ : C, 58.54; H, 3.51; N, 14.63; F,6.61%. Found: C, 58.29; H, 3.47; N, 14.69; F, 6.70%.

EXAMPLE IV

Ethyl 8-Fluoropyrimido[4,5-b]Quinolin-4(3H)-One-2-Carboxylate

A. α-cyano-β-(2-Nitro-4-Fluorophenyl)Acrylamide

A mixture of 4-fluoro-2-nitrobenzaldehyde (8.70 g., 51.5 millimoles),2-cyanoacetamide (4.7 g., 54.4 millimoles), piperidine (0.032 g., 0.37millimole) and ethanol (80 ml.) is stirred at room temperature for 28hours. The solid which formed is separated by filtration, washed withethanol (45 ml.) and dried. Yield = 10 g. (83.5%) of the titleacrylamide as light tan crystals M.P. 278°-279° C.

b. 7-fluoro-2-Aminoquinoline-3-Carboxamide

To a solution of the product of Preparation A above (10.0 g., 0.042mole) in acetic acid (192 ml.) at 110° C. is gradually added, over aforty minute period, iron powder (10.3 g., 0.192 mole). The mixture isstirred for one hour and then concentrated under reduced pressure to athick paste. The paste is partitioned between ethyl acetate (100 ml.)and water (100 ml.) and the phases separated. This partition step isrepeated three more times. The combined ethyl acetate layers are dried(Na₂ SO₄), filtered and concentrated to small volume. The solid filteredoff and dried. Yield = 4.72 g. (57.3%) of crude product; m.p. 259°-262°C. It is used directly in the succeeding step.

C. ethyl 8-fluoropyrimido[4,5-b]quinolin-4(3H)-one-2carboxylate

Diethyl oxalate (47.5 g., 0.326 mole) and7-fluoro-2-aminoquinoline-3-carboxamide (3.7 g., 0.015 mole) are mixedtogether and heated at 160° C. for seven hours. The reaction mixture iscooled to room temperature, hexane (300 ml.) added, and the brown solidwhich precipitates filtered off, and washed with hexane (60 ml.). It isthen slurried in hot chloroform (250 ml.) and the insoluble materialremoved by filtration. The hot filtrate is decolorized with charcoal,filtered and dried (Na₂ SO₄). The light brown solid which precipitatesupon cooling is filtered off and recrystallized from isopropyl alcohol.Yield = 1.04 g. (29.2%) of the title ethyl ester. M.P. 248°-251° C.

Analysis: Calcd. for C₁₄ H₁₀ FN₃ O₃ : C, 58.54; H, 3.51; N, 14.63; F,6.61%. Found: C, 58.52; H, 3.61; N, 14.76; F, 6.56%.

EXAMPLE V Ethyl 7-Chloropyrimido[4,5-b]Quinolin-4(3H)-One-2-Carboxylate

A. α-cyano-β-(2-Nitro-5-Chlorophenyl)Acrylamide

A mixture of 5-chloro-2-nitrobenzaldehyde (47.0 g., 0.25 mole),2-cyanoacetamide (21.0 g., 0.25 mole), diethylamine (0.5 ml.) andethanol (500 ml) is heated at reflux for one hour. Sodium ethoxide (10mg.) is added to the clear mixture and refluxing continued for anadditional 2.5 hours. It is then cooled and the crystalline productwhich precipitates recovered by filtration. Yield = 52.3 g. (88%); m.p.of crude = 183°-185° C. It is used without purification in step B.

b. 6-chloro-2-Aminoquinoline-3 -Carboxamide

Following the procedure of Example IV-B,α-cyano-β-(2-nitro-5-chlorophenyl)acrylamide (51.0 g., 0.2mole) istreated with iron powder (56 g., 1.0 mole) to provide 19 g. (43%) of thetitle carboxamide derivative M.P. 250°-251° C. when recrystallized fromethanol.

C. ethyl 7-Chloropyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate

A mixture of 6-chloro-2-aminoquinoline-3-carboxamide (2.2 g., 0.01mole), sodium hydride (0.52 g., 0.012 mole as 56% dispersion in oil) andN,N-dimethylformamide (20 ml.) is added to a solution of diethyl oxalate(5 ml.) and N,N-dimethylformamide (5 ml.). The reaction mixture isstirred for fifteen minutes, a second portion of sodium hydride (0.52g., 0.012 mole) added and stirring continued for an additional fifteenminutes. Acetic acid (25.0 ml.) is cautiously added to the mixturefollowed by water (50 ml.). The tan precipitate is removed by filtrationand dried (2.0 g. of crude ester). It is purified by chromatography onsilica gel using chloroform:2B ethanol (99:1) as eluant. The product,recovered by concentration of the eluate, is recrystallized from aceticacid. Yield = 1.3 g. (37.3%). M.P. 260.5° C. (dec.). Mass spectra gavem/e = 303.

EXAMPLE VI Ethyl7,8-Methylenedioxypyrimido[4,5-b]Quinolin-4(3H)-One-2-Carboxylate

A. 6,7-methylenedioxy-2-Aminoquinoline-3-Carboxamide

To sodium methoxide (1.90 g., 0.03 mole) in methanol (50 ml.) is added4,5-methylenedioxy-2-aminobenzaldehyde (5.0 g., 0.03 mole) and2-cyanoacetamide (2.50 g., 0.03 mole). The mixture is heated to refluxfor fifteen minutes and then cooled in an ice bath. The bright yellowsolid is filtered off and recrystallized from acetic acid to give 6.18g. (89.3%) of the desired product. M.P. 308° C. (dec.). (m/e = 231)

B. (cyclization of 6,7-methylenedioxy-2-aminoquinoline-3-carboxamide

A mixture of 6,7-methylenedioxy-2-aminoquinoline-3-carboxamide (1.50 g.,6.5 millimoles), sodium methoxide (0.05 g., 1.25 millimoles) and diethyloxalate (150 ml.) is heated to 150° C. for 3.5 hours. The mixture isthen cooled to room temperature to precipitate the product which isrecovered by filtration (1.0 g.). It is purified by chromatography onsilica gel using chloroform:methanol (99:1) as eluant. The product isrecovered by evaporation of the eluate and recrystallization of theresidue from ethanol. Yield = 0.414 g. (20.4%) of the cyclized product.M.P. 267° C. (dec.).

Analysis: Calcd. for C₁₅ H₁₁ N₃ O₅ : C, 57.51; H, 3.54; N, 13.41%.Found: C, 57.19; H, 3.67; N, 13.33%.

EXAMPLE VII 7,8-Dimethoxypyrimido[4,5-b]Quinolin-4(3H)-One-2-Carboxamide

Anhydrous ammonia is bubbled into a mixture of ethyl7,8-dimethoxypyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate (300 mg.,9.00 millimoles) in absolute ethanol (75 ml.) for fifteen minutes. Aclear solution formed followed after a few minutes by formation of aprecipitate. The reaction mixture is transferred to a pressure bomb(Monel) and heated in a 95° C. oil bath overnight. The bomb is thencooled to room temperature and the contents removed. The bomb is washedwith ethanol and the combined reaction mixture plus wash filtered torecover the product. The filter cake is washed with ethanol and thendried in air. Yield = 260 mg. (95%). M.P. 310° C. (dec.).

EXAMPLE VIII n-Butylpyrimido[4,5-b]Quinolin-4(3H)-One-2-Carboxylate

Ethylpyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate (3.0 g., 1.12millimoles) is added to n-butanol (350 ml.) containing ten drops ofhydrochloric acid. The mixture is refluxed for 36 hours, and then cooledand filtered. The solid is dissolved in hot chloroform, the insolublematter removed by filtration and the filtrate concentrated to provide1.19 g. of the n-butyl ester (36% yield). M.P. 218-219.5° C.

Analysis: Calcd. for C₁₆ H₁₅ N₃ O₃ : C, 64.71; H, 5.09%. Found: C,64.12; H, 5.20%.

EXAMPLE IX Pyrimido[4,5-b]Quinolin-4(3H)-One-2-Carboxamide

A mixture of 2-aminoquinoline-3-carboxamide (2.0 g., 1.15 millimoles)ethyl oxamate (2.71 g., 23.1 millimoles), ethylene glycol (10 ml.) andsodium methoxide (10 mg.) is heated at 170° C. for one hour. The productis precipitated by slow addition of ice cold methanol (50 ml.) to thehot reaction mixture followed by chilling in an ice bath. It is filteredoff, washed with cold methanol and dried in vacuo. Yield = 0.768 g.(28%). M.P. 320° C.

Analysis: Calcd. for C₁₂ H₈ O₂ N₄ : C, 59.96; H, 3.35; N, 23.32%. Found:C, 59.90; H, 3.43; N, 22.10%.

EXAMPLE X Ethyl 6-Chloropyrimido[4,5-b]Quinolin-4(3H)-One-2-Carboxylate

A. 5-chloro-2-Aminoquinoline-3-Carboxamide

Following the procedure of Example I-A, 2-amino-6-chlorobenzaldehyde(5.4 g., 0.035 mole), 2-cyanoacetamide (2.94 g., 0.035 mole), sodiumethoxide (3.0 g., 0.044 mole) in ethanol (50 ml.), the title carboxamideis prepared in 77% yield (5.92 g.). M.P. 270°-273° C. (dec.).

B. ethyl 6-Chloropyrimido[4,5-b]quinolin-4(3H)-One-2-Carboxylate

Diethyl oxalate (350 ml.) and 5-chloro-2-aminoquinoline-3-carboxamide(5.9 g., 0.0267 mole) are heated together at 170° C. for four hours.By-product water and ethanol are distilled from the reaction mixture.The dark reaction mixture is cooled, treated with hexane (300 ml.) andfiltered. The brown solid is dissolved in methylene chloride:ethanol(1:1), decolorized with charcoal and concentrated to give a tan solid.The solid is recrystallized from methylene chloride-hexane. It ispurified further by chromatography on silica gel using methylenechloride:ethanol (9:1) as eluant. The product, recovered by evaporationof the eluate, is recrystallized from methylene chloride-ethanol. Yield= 0.756 g. (9.3%). M.P. 278°-279° C. (dec.).

Analysis: Calcd. for C₁₄ H₁₀ ClN₃ O₃ : C, 55.50; H, 3.33; N, 13.87%.Found: C, 55.03; H, 3.21; N, 13.85%.

EXAMPLE XI Pyrimido[4,5-b]Quinolin-4(3H)-One-2-Carboxylic Acid DisodiumSalt

Ethyl pyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate (5.0 g., 0.0185mole) is added to 15 % aqueous sodium hydroxide (200 ml.) and themixture stirred for twenty hours at room temperature. The yellow solidwhich formed is filtered from the reaction mixture, dissolved in water,and the solution adjusted to pH 7 by slow addition of 10% hydrochloricacid. The precipitate is filtered and triturated with methanol. Theslurry is filtered, the filter cake washed with methanol and dried.Yield = 4.0 g. (73.4% of the disodium hemi-hydrate salt. M.P. 345°-347°C., (dec.).

EXAMPLE XII Ethyl7-Methoxypyrimido[4,5-b]Quinolin-4(3H)-One-2-Carboxylate

A. α-cyano-β-(5-Methoxy-2-Nitrophenyl)Acrylamide

Following the procedure of Example II-A, 5-methoxy-2-nitrobenzaldehydeis converted to the title acrylamide derivative in 86% yield. M.P.207°-208° C. (dec.)

B. 6-methoxy-2-Aminoquinoline-3-Carboxamide

α-Cyano-β-(5-methoxy-2-nitrophenyl)acrylamide is reacted according tothe procedure of Example II-B to give the corresponding quinolinederivative in 79.5% yield. M.P. 231°-232° C. (dec.).

C. ethyl-7-Methoxypyrimido[4,5-b]-Quinolin-4(3H)-One-2-Carboxylate

6-Methoxy-2-aminoquinoline-3-carboxamide is converted to the titlecompound by the procedure of Example II-C in 10% yield. M.P. 263°-264°C. (dec.).

Analysis: Calcd. for C₁₅ H₁₃ N₃ O₄ : C, 60.19; H, 4.38; N, 14.04%.Found: C, 60.28; H, 4.34; N, 14.26%.

EXAMPLE XIII Ethyl8,9-Dimethoxypyrimido[4,5-b]-Quinolin-4(3H)-One-2-Carboxylate

The procedures of Example II-A-C are repeated but using2-nitroveratraldehyde (2.08 g.) in place of 6-nitroveratraldehyde. Theyields of melting points of the intermediates and final product arelisted below:

A. α-cyano-β-(2-nitro-3,4-dimethoxyphenyl)acrylamide: Yield = 64%; M.P.194°-195° C.

B. 7,8-dimethoxy-2-aminoquinoline-3-carboxamide: Yield = 50%; M.P.218°-219° C.

C. ethyl-8,9-dimethoxypyrimido[4,5-b]-quinolin-4(3H)-one-2-carboxylate;Yield = 30%; M.P. 233°-234° C. (dec.).

Analysis: Calcd. for C₁₆ H₁₅ N₃ O₃ : C, 58.35; H, 4.60; N, 12.76%.Found: C, 58.52; H, 4.47; N, 12.68%.

EXAMPLE XIV7,8-Dimethoxypyrimido-[4,5-b]-Quinolin-4(3H)-One-2-Hydroxamic Acid

Ethyl 7,8-dimethoxypyrimido-[4,5-b]quinolin-4(3H)-one-2-carboxylate (200mg., 6.08 millimoles) is added to a solution of hydroxylaminehydrochloride (69 mg., 100 millimoles) and triethylamine (100 mg., 100millimiles) in absolute ethanol (50 ml.). The mixture is heated at 95°C. overnight in a bomb and then cooled. The insoluble yellow solid isfiltered off, washed with hot ethanol and dried to provide 143 mg. (74%)of the title product. M.P. 337° C. (dec.).

EXAMPLE XV Ethyl7-Hydroxy-8-Methoxypyrimido[4,5-b]Quinolin-4(3H)One-2-CarboxylateTrifluoroacetate

A solution of ethyl 7-benzyloxy-8-methoxypyrimido[4,5-b]quinolin-4(3H)one-2-carboxylate (250 mg., 0.618 mmole) in trifluoroacetic acid (5 ml.)is refluxed for 2.5 hours. (Alternatively the mixture is stirred at roomtemperature for three days). The reaction mixture is then poured intoether (25 ml.) and the resulting bright yellow precipitate of thetrifluoroacetate salt recovered by filtration, washed with ether anddried. Yield = 194 mg., 72%; m.p. 279° C.

Analysis: Calcd. for C₁₅ H₁₃ N₃ O₅ CF₃ COOH 1/2 H₂ O: C, 46.58; H, 3.42;N, 9.58%. Found: C, 46.81; H, 3.41; N, 9.21%.

Repetition of the above procedure but using the corresponding n-butylester (862 mg., 0.199 mmole) in place of the ethyl ester, 8 ml.trifluoroacetic acid and a reflux period of 3.5 hours affords n-butyl7-hydroxy-8-methoxypyrimido[4,5-b]quinolin-4(3H)one-2-carboxylatetrifluoroacetate (0.67 g., 74%); m.p. 240°- 241° C. (dec.)

Analysis: Calcd. for C₁₇ H₁₇ O₅ N₃ CF₃ COOH: C, 49.89; H, 3.96; N, 9.18;F, 12.46% C, 49.93; H, 3.97; N, 8.79; F, 11.17%.

Similarly, ethyl 7-benzyloxpyrimido-[4,5-b]quinolin-4(3H)one-2-carboxylate is debenzylated to give a 74% yield of ethyl7-hydroxypyrimido [4,5-b]quinolin-4(3H)one-2-carboxylatehemitrifluoroacetate; m.p. 274°-275° C. (dec.)

Analysis: Calcd. for C₁₄ H₁₁ O₄ N₃ 1/2 CF₃ COOH: C, 57.43; H, 3.66; N,13.39% C, 57.75; H, 4.05; N, 13.65%.

EXAMPLE XVI7-Hydroxy-8-Methoxypyrimido[4,5-b]Quinolin-4(3H)One-2-Carboxylic Acid

The trifluoroacetate-hemihydrate salt of ethyl7-hydroxy-8-methoxypyrimido[4,5-b]quinolin-4(3H)one-2-carboxylate (200mg., 0.456 mmole) is slurried in 0.1N sodium hydroxide (5 ml.) and 15%sodium hydroxide added dropwise with stirring until solution iscomplete. The mixture is stirred at room temperature for 18 hours and isthen made strongly acid by addition of trifluoroacetic acid. Theprecipitate which forms is separated by filtration, washed with waterand then with isopropyl alcohol and air-dried. Yield = 114 mg.; m.p.281° C. (dec.).

Analysis: Calcd. for C₁₃ H₉ O₅ N₃ 2H₂ O: C, 48.29; H, 4.02; N, 13.00%Found C, 47.3; H, 3.32; N, 12.73%.

In like manner, ethyl7-hydroxypyrimido[4,5-b]quinolin-4(3H)one-2-carboxylatehemitrifluoroacetate (210 mg.) is converted to7-hydroxypyrimido[4,5-b]quinolin-4(3H)one-2-carboxylic acid. Yield - 191mg., 91%; m.p. 340° C. (dec.)

EXAMPLE XVII Ethyl7-Methoxy-8-Hydroxypyrimido[4,5-b]Quinolin-4(3H)One-2-Carboxylate

A solution of ethyl7-methoxy-8benzyloxypyrimido[4,5-b]quinolin-4(3H)one-2-carboxylate (198mg., 0.488 mmole) in trifluoroacetic acid (4 ml.) is stirred at roomtemperature for 8 days. Ether (15 ml.) is added and the yellowprecipitate which forms separated by filtration. It is taken up inchloroform and the solution filtered through diatomaceous earth toremove a small amount of insoluble material. The filtrate is decolorizedwith charcoal and concentrated under reduced pressure to small volume.The solid which forms is filtered and dried; 9 mg., 6% yield; m.p. 265°-266° C. (dec.).

EXAMPLE XVIII

The compounds below are prepared from appropriate reactants by theprocedures of the preceding examples.

    ______________________________________                                         ##STR9##                                                                                                              Meth-                                R°                                                                             R.sub.2  R.sub.3   R.sub.4 R.sub.5                                                                             of Ex.                               ______________________________________                                        OCH.sub.3                                                                             H        H         H       H     I                                    NHOH    H        H         H       H     XIV                                  OCH.sub.3                                                                             H        F         H       H     III                                  NH.sub.2                                                                              H        F         H       H     VII                                  O-n-C.sub.4 H.sub.9                                                                   H        H         F       H     VIII                                 NH.sub.2                                                                              H        H         F       H     VII                                  NH.sub.2                                                                              Cl       H         H       H     VII                                  NHOH    Cl       H         H       H     XIV                                  O-i-C.sub.3 H.sub.7                                                                   H        Cl        H       H     V                                    NH.sub.2                                                                              H        Cl        H       H     IX                                   OCH.sub.3                                                                             H        OCH.sub.2O      H     VI                                     NH.sub.2                                                                              H        OCH.sub.2O      H     IX                                     NHOH    H        OCH.sub.2O      H     XIV                                    OCH.sub.3                                                                             H        OCH.sub.3 OCH.sub.3                                                                             H     II                                   O-n-C.sub.3 H.sub.7                                                                   H        OCH.sub.3 OCH.sub.3                                                                             H     II                                   NH.sub.2                                                                              H        OCH.sub.3 OCH.sub.3                                                                             H     IX                                   NH.sub.2                                                                              H        OCH.sub.3 H       H     VII                                  NH.sub.2                                                                              H        H         OCH.sub.3                                                                             OCH.sub.3                                                                           VII                                  OC.sub.2 H.sub. 5                                                                     H        OC.sub.2 H.sub.5                                                                        H       H     II                                   OC.sub.2 H.sub.5                                                                      H        H         OC.sub.2 H.sub.5                                                                      H     II                                   NH.sub.2                                                                              H        OC.sub.2 H.sub.5                                                                        OC.sub.2 H.sub.5                                                                      H     VII                                  NHOH    H        OC.sub.2 H.sub.5                                                                        OC.sub.2 H.sub.5                                                                      H     XIV                                  OC.sub.2 H.sub.5                                                                      H        Br        H       Br    I                                    OC.sub.2 H.sub.5                                                                      H        Cl        H       Cl    I                                    OCH.sub.3                                                                             Cl       H         H       Cl    I                                    OC.sub.2 H.sub.5                                                                      H        H         H       OCH.sub.3                                                                           II                                   NH.sub.2                                                                              H        H         H       OCH.sub.3                                                                           VII                                  NH.sub.2                                                                              H        H         OC.sub.2 H.sub.5                                                                      H     VII                                  OCH.sub.3                                                                             H        H         Cl      H     V                                    O-n-C.sub.3 H.sub.7                                                                   OCH.sub.3                                                                              H         H       OCH.sub.3                                                                           II                                   OC.sub.2 H.sub.5                                                                      H        H         I       H     II                                   OC.sub.2 H.sub.5                                                                      Br       H         H       H     V                                    NH.sub.2                                                                              Br       H         H       H     VII                                  OC.sub.2 H.sub.5                                                                      OCH.sub.3                                                                              OCH.sub.2O      H     I                                      NH.sub.2                                                                              OCH.sub.3                                                                              OCH.sub.2O      H     VII                                    O-i-C.sub.3 H.sub.7                                                                   H        CH.sub.3  H       H     VIII                                 NH.sub.2                                                                              H        CH.sub.3  H       H     VII                                  OC.sub.2 H.sub. 5                                                                     H        H         CH.sub.3                                                                              H     I                                    OC.sub.2 H.sub.5                                                                      CH.sub.3 H         H       H     I                                    NH.sub.2                                                                              CH.sub.3 H         H       H     IX                                   NHOH    CH.sub.3 H         H       H     XIV                                  OC.sub.2 H.sub.5                                                                      H        t-C.sub.4 H.sub.9                                                                       H       H     I                                    NH.sub.2                                                                              H        t-C.sub.4 H.sub.9                                                                       H       H     VII                                  OCH.sub.3                                                                             CH.sub.3 H         CH.sub.3                                                                              H     I                                    OC.sub.2 H.sub.5                                                                      CH.sub.3 CH.sub.3  H       H     I                                    NH.sub.2                                                                              CH.sub.3 CH.sub.3  H       H     VII                                  OC.sub.2 H.sub.5                                                                      H        C.sub.2 H.sub.5                                                                         H       H     I                                    NH.sub.2                                                                              H        C.sub.2 H.sub.5                                                                         H       H     IX                                   NHOH    H        n-C.sub.3 H.sub.7                                                                       H       H     XIV                                  OC.sub.2 H.sub.5                                                                      H        n-C.sub.3 H.sub.7                                                                       n-C.sub.3 H.sub.7                                                                     H     VII                                  NH.sub.2                                                                              H        n-C.sub.3 H.sub.7                                                                       n-C.sub.3 H.sub.7                                                                     H     IX                                   OC.sub.2 H.sub.5                                                                      H        H         C.sub.2 H.sub.5                                                                       H     I                                    OC.sub.2 H.sub.5                                                                      H        H         i-C.sub.3 H.sub.7                                                                     H     I                                    OC.sub.2 H.sub.5                                                                      OCH.sub.2O     OCH.sub.3 H     I                                      O-n-C.sub.4 H.sub.9                                                                   OCH.sub.2O     OCH.sub.3 H     VIII                                   NH.sub. 2                                                                             OCH.sub.2O     OCH.sub.3 H     VII                                    NH.sub.2                                                                              OCH.sub.2O     H         H     VII                                    NH.sub.2                                                                              H        OCH.sub.2CH.sub.2O                                                                            H     II                                     OCH.sub.3                                                                             OCH.sub.3                                                                              OCH.sub.3 OCH.sub.3                                                                             H     I                                    NH.sub.2                                                                              OCH.sub.3                                                                              OCH.sub.3 OCH.sub.3                                                                             H     VII                                  O-n-C.sub.3 H.sub.7                                                                   H        CH.sub.3  CH.sub.3                                                                              H     I                                    OC.sub.2 H.sub.5                                                                      Br       H         H       H     I                                    OC.sub.2 H.sub.5                                                                      H        Br        H       H     I                                    NH.sub.2                                                                              H        Br        H       H     VII                                  OC.sub.2 H.sub.5                                                                      H        H         Br      H     I                                    NHOH    H        H         Br      H     XIV                                  OCH.sub.3                                                                             H        H         t-C.sub.4 H.sub.9                                                                     H     II                                   OC.sub.2 H.sub.5                                                                      H        OCH.sub.3 OC.sub.2 H.sub.5                                                                      H     II                                   OCH.sub.3                                                                             H        Cl        Br      Cl    II                                   OCH.sub.3                                                                             H        H         O-i-C.sub.3 H.sub.7                                                                   OCH.sub.3                                                                           II                                   OC.sub.2 H.sub.5                                                                      OCH.sub.3                                                                              OCH.sub.2O      OCH.sub.3                                                                           II                                     OC.sub.2 H.sub.5                                                                      H        O-n-C.sub.4 H.sub.9                                                                     O-n-C.sub.4 H.sub.9                                                                   H     II                                   OC.sub.2 H.sub. 5                                                                     H        H         Cl      H     II                                   OC.sub.2 H.sub.5                                                                      H        H         Cl      Cl    II                                   O-n-C.sub.4 H.sub.9                                                                   H        SCH.sub.3 H       H     II                                   NH.sub.2                                                                              H        SCH.sub.3 H       H     VII                                  OCH.sub.3                                                                             H        SCH.sub.3 SCH.sub.3                                                                             H     II                                   NHOH    H        SCH.sub.3 SCH.sub.3                                                                             H     XIV                                  OC.sub.2 H.sub.5                                                                      H        H         H       SCH.sub.3                                                                           II                                   OC.sub.2 H.sub.5                                                                      H        H         OC.sub.7 H.sub.7                                                                      OCH.sub.3                                                                           II                                   O-n-C.sub.3 H.sub.7                                                                   H        H         OC.sub.7 H.sub.7                                                                      H     II                                   O-n-C.sub.4 H.sub.9                                                                   F        H         H       H     II                                   OCH.sub.3                                                                             OC.sub.7 H.sub.7                                                                       OCH.sub.3 H       H     II                                   OC.sub.2 H.sub.5                                                                      H        OC.sub.7 H.sub.7                                                                        OC.sub.7 H.sub.7                                                                      H     II                                   OC.sub.2 H.sub.5                                                                      OC.sub.7 H.sub.7                                                                       H         H       H     II                                   OC.sub.2 H.sub.5                                                                      OC.sub.7 H.sub.7                                                                       Br        H       Br    II                                   OCH.sub.3                                                                             H        OCH.sub.3 OC.sub.7 H.sub.7                                                                      Br    II                                   OCH.sub.3                                                                             H        OC.sub.7 H.sub.7                                                                        H       II                                         OC.sub.2 H.sub.5                                                                      OC.sub.7 H.sub.7                                                                       OCH.sub.3 OCH.sub.3                                                                             H     II                                   OC.sub.2 H.sub.5                                                                      H        Br        H       OC.sub.7 H.sub.7                                                                    I                                    O-n-C.sub.4 H.sub.9                                                                   H        H         H       OC.sub.7 H.sub. 7                                                                   I                                    O-n-C.sub.3 H.sub.7                                                                   C.sub.2 H.sub.5                                                                        H         OC.sub.7 H.sub.7                                                                      H     III                                  O-n-C.sub.3 H.sub.7                                                                   C.sub.2 H.sub.5                                                                        OC.sub.7 H.sub.7                                                                        H       H     III                                  OC.sub.2 H.sub.5                                                                      H        OC.sub.7 H.sub.7                                                                        OC.sub.2 H.sub.5                                                                      H     II                                   OC.sub.2 H.sub.5                                                                      H        OC.sub.2 H.sub.5                                                                        OC.sub.7 H.sub.7                                                                      H     II                                   OC.sub.2 H.sub.5                                                                      H        F         OC.sub.7 H.sub.7                                                                      H     II                                   OC.sub.2 H.sub.5                                                                      H        Br        OC.sub.7 H.sub.7                                                                      H     II                                   OCH.sub.3                                                                             H        Cl        OC.sub.7 H.sub.7                                                                      H     VII                                  NH.sub.2                                                                              H        OC.sub.7 H.sub.7                                                                        H       OCH.sub.3                                                                           VII                                  NH.sub.2                                                                              H        OCH.sub.3 OC.sub.7 H.sub.7                                                                      H     IX                                   NHOH    H        OCH.sub.3 OC.sub.7 H.sub.7                                                                      H     XIV                                  NHOH    H        OC.sub.7 H.sub.7                                                                        OCH.sub.3                                                                             H     XIV                                  NHOH    OC.sub.7 H.sub.7                                                                       OCH.sub.3 OCH.sub.3                                                                             H     XIV                                  NHOH    H        OC.sub.2 H.sub.5                                                                        OC.sub.7 H.sub.7                                                                      H     XIV                                  NH.sub.2                                                                              H        OC.sub.7 H.sub.7                                                                        OC.sub.2 H.sub.5                                                                      H     VII                                  NH.sub.2                                                                              H        F         OC.sub.7 H.sub.7                                                                      H     VII                                  NHOH    H        Cl        OC.sub.7 H.sub.7                                                                      H     XIV                                  NH.sub.2                                                                              H        OC.sub.7 H.sub. 7                                                                       OCH.sub.3                                                                             H     VII                                  NH.sub.2                                                                              H        Cl        OCH.sub.3                                                                             H     VII                                  OC.sub.2 H.sub.5                                                                      H        SC.sub.7 H.sub.7                                                                        H       H     II                                   NH.sub.2                                                                              H        H         H       SC.sub.7 H.sub.7                                                                    VII                                  OC.sub.2 H.sub.5                                                                      H        SC.sub.7 H.sub.7                                                                        C.sub.2 H.sub.5                                                                       H     II                                   OC.sub.2 H.sub.5                                                                      H        H         SC.sub.7 H.sub.7                                                                      H     II                                   NHOH    H        H         SC.sub.7 H.sub.7                                                                      H     XIV                                  OC.sub.2 H.sub.5                                                                      SC.sub.7 H.sub.7                                                                       H         H       SC.sub.7 H.sub.7                                                                    II                                   NH.sub.2                                                                              SC.sub.7 H.sub.7                                                                       H         H       SC.sub.7 H.sub.7                                                                    XIV                                  ______________________________________                                    

the benzyl ethers and benzylthio ethers tabulated above are converted tothe corresponding hydroxy and thiol compounds by the procedure ofExample XV.

The thus-produced hydroxy and thiol substituted 2-carboxylic acid estersare hydrolzyed to the corresponding 2-carboxylic acid derivatives by theprocedure of Example XVI.

EXAMPLE XIX Ethyl7-Acetoxy-8-Methoxypyrimido[4,5-b]Quinolin-4(3H)One-2-Carboxylatep-Toluenesulfonate

A mixture of acetic anhydride (4 ml.), ethyl7-hydroxy-8-methoxypyrimido[4,5-b]quinolin-4(3H)one-2-carboxylatetrifluoroacetate hemihydrate (250 mg. 0.572 mmole) and p-toluenesulfonicacid monohydrate (100 mg., 0.572 mmole) is heated at 100° C. for 24hours. The acetic anhydride is then stripped from the reaction mixturein vacuo. The solid residue is dissolved in hot chloroform and thesolution decolorized with activated charcoal. Benzene (4 volumes) isadded to the decolorized solution which is then chilled in ice. Thecrystals which separate are recovered by filtration and air dried. Yield= 174 mg., 58%; m.p. 215°-217° C.

Analysis: Calcd. for C₁₇ H₁₅ O₆ N₃ C₇ H₈ O₃ S: C, 54.43; H, 4.37; N,7.98% Found C, 53.74; H, 4.28; N, 7.24%.

The above procedure is repeated but using the corresponding n-butylester trifluoroacetate salt (200 mg., 0.437 mmole) in place of the ethylester trifluoroacetate salt. The product is recovered by concentrationof the chloroform solution to 1/3 volume and filtration of the solidwhich precipitates rather than by precipitation with benzene. Yield - 30mg., 18%; m.p. 260°- 261° C. (dec.)

The above procedure is repeated but using the appropriate acid anhydrideand in place of acetic anhydride and the appropriate hydroxy or thiolformula I compound as reactant to give the following compounds:

    __________________________________________________________________________     ##STR10##                                                                    R.sub.1                                                                            R.sub.2                                                                              R.sub.3                                                                              R.sub.4                                                                              R.sub.5                                                                              R                                            __________________________________________________________________________    H    H      C.sub.2 H.sub.5 COO                                                                  OCH.sub.3                                                                            H      COOC.sub.2 H.sub.5                           H    H      C.sub.3 H.sub.7 COO                                                                  OCH.sub.3                                                                            H      COOC.sub.2 H.sub.5                           H    H      HCOO   OCH.sub.3                                                                            H      COOC.sub.2 H.sub.5                           H    H      OCH.sub.3                                                                            CH.sub.3 COO                                                                         H      COOC.sub.2 H.sub.5                           H    H      OCH.sub.3                                                                            C.sub.2 H.sub.5 COO                                                                  H      COOC.sub.2 H.sub.5                           H    H      OCH.sub.3                                                                            HCOO   H      COOC.sub.2 H.sub.5                           H    H      HCOO   OCH.sub.3                                                                            H      COO-n-C.sub.4 H.sub.9                        H    H      CH.sub.3 COO                                                                         OCH.sub.3                                                                            H      COO-n-C.sub.4 H.sub.9                        C.sub.6 H.sub.5                                                                    H      HCOO   H      H      CH.sub.3                                     C.sub.6 H.sub.5                                                                    H      C.sub.3 H.sub.7 COO                                                                  OCH.sub.3                                                                            H      CH.sub. 3                                    H    H      H      HCOO   H      COO-n-C.sub.3 H.sub.7                        H    H      H      CH.sub.3 COO                                                                         H      COO-n-C.sub.3 H.sub.7                        C.sub.6 H.sub.5                                                                    H      H      CH.sub.3 COO                                                                         OCH.sub.3                                                                            CH.sub.3                                     H    H      CH.sub.3 COO                                                                         CH.sub.3 COO                                                                         H      COOC.sub.2 H.sub.5                           H    H      HCOO   HCOO   H      COOC.sub.2 H.sub.5                           H    H      OCH.sub.3                                                                            CH.sub.3 COO                                                                         Br     COOCH.sub.3                                  H    CH.sub.3 COO                                                                         OCH.sub.3                                                                            H      H      C.sub.2 H.sub.5                              CH.sub.3                                                                           H      C.sub.6 H.sub.5 COO                                                                  OCH.sub.3                                                                            H      C.sub.2 H.sub.5                              n-C.sub.4 H.sub.9                                                                  H      C.sub.6 H.sub.5 COO                                                                  OCH.sub.3                                                                            H      C.sub.2 H.sub.5                              C.sub.6 H.sub.5                                                                    H      CH.sub.3 COO                                                                         H      H      C.sub.2 H.sub.5                              H    C.sub.3 H.sub.7 COO                                                                  OCH.sub.3                                                                            H      H      COOCH.sub.3                                  H    CH.sub.3 COO                                                                         OCH.sub.3                                                                            OCH.sub.3                                                                            H      COOC.sub.2 H.sub.5                           H    H      Br     H      CH.sub.3 COO                                                                         COOC.sub.2 H.sub.5                           H    H      H      H      HCOO   COO-n-C.sub.4 H.sub.9                        H    H      H      H      C.sub.3 H.sub.7 COO                                                                  COO-n-C.sub.4 H.sub.9                        H    C.sub.2 H.sub.5                                                                      H      CH.sub.3 COO                                                                         H      COOC.sub.2 H.sub.5                           CH.sub.3                                                                           H      CH.sub.3 COO                                                                         OC.sub.2 H.sub.5                                                                     H      CH.sub.3                                     C.sub.2 H.sub.5                                                                    H      F      CH.sub.3 COO                                                                         H      C.sub.2 H.sub.5                              n-C.sub.4 H.sub.9                                                                  C.sub.2 H.sub.5                                                                      CH.sub.3 COO                                                                         H      H      C.sub.2 H.sub.5                              H    H      Cl     CH.sub.3 COO                                                                         H      COOCH.sub.3                                  C.sub.2 H.sub.5                                                                    H      F      C.sub.3 H.sub.7 COO                                                                  H      COOC.sub.2 H.sub.5                           H    C.sub.2 H.sub.5                                                                      HCOO   H      H      COO-n-C.sub.3 H.sub.7                        H    H      CH.sub.3 COO                                                                         H      H      COO-n-C.sub.3 H.sub.7                        H    H      C.sub.3 H.sub.7 COO                                                                  H      H      COO-n-C.sub.3 H.sub.7                        H    H      CH.sub.3 COO                                                                         H      H      COOCH.sub.3                                  H    H      C.sub.3 H.sub.7 COO                                                                  H      H      COOCH.sub.3                                  H    H      CH.sub.3 COO                                                                         CH.sub.3 COO                                                                         H      COOCH.sub.3                                  H    H      H      C.sub.2 H.sub.5 COO                                                                  H      COOC.sub.2 H.sub.5                           CH.sub.3                                                                           H      C.sub.6 H.sub.5 COO                                                                  OCH.sub.3                                                                            H      COOC.sub.2 H.sub.5                           H    H      OCH.sub.3                                                                            C.sub.6 H.sub.5 COO                                                                  H      COOC.sub.2 H.sub.5                           H    H      Cl     C.sub.6 H.sub.5 COO                                                                  H      COOC.sub.2 H.sub.5                           __________________________________________________________________________

example xx 2-hydroxyethyl 7,8-Dimethoxy-pyrimidin[4,5-b]quinolin-4-(3H)-One-2-Carboxylate

Triethylamine (1 ml.) is added to a slurry of ethyl7,8-dimethoxypyrimidin [4,5-b]quinoline-4(3H)-One-2-carboxylate (500mg.) in ethylene glycol (5 ml.). The mixture is stirred for 6 hours andis then diluted with water (30 ml.). The resulting clear yellow solutionis acidified with acetic acid and the precipitate which forms filteredoff. It is recrystallized while still damp from N,N-dimethylformamide(20 ml.). Yield = 285 mg. (53.5%) m.p. 252° C.

Analysis: Calcd. for C₁₆ H₁₅ N₃ O₆ ; C, 55.65 ; H, 4.48; N, 12.17%.Found: C, 55.35; H, 4.51; N, 12.39%.

In like manner, the alkyl esters of Example II-XIX, XXI-XXIII andXXVII-XXXII are transesterified to the corresponding 2-hydroxyethylesters. Replacement of ethylene glycol by propylene glycol, butyleneglycol or 1,4-dihydroxybutane affords the corresponding hydroxyalkylesters.

EXAMPLE XXI Ethyl7-Methylthiopyrimido[4,5-b]quinolin-4(3H)-One-2-Carboxylate

A. α-cyano-β-(2-Nitro-5-Methylthiophenyl)acrylamide

A solution of the sodium salt of methylmercaptan (2.78g, 0.0398 Mole) inN,N-dimethylformamide (50 ml.) is prepared by bubbling methylmercaptaninto a mixture of sodium hydride (1.67 g. of 57% NaH) inN,N-dimethylformamide (50 ml.). The reaction mixture is cooled by meansof an ice-bath until the reaction is complete.

The sodium methylmercaptide solution is then added dropwise to a mixtureof α-cyano-β-(2-nitro-5-chlorophenyl)acrylamide (10 g., 0.0398 mole) inN,N-dimethylformamide (35 ml.) cooled in an ice-bath. The mixture isstirred for one hour and then removed from the ice-bath and stirred foran additional two hours. The reaction mixture is poured into water (600ml.) and the resulting mixture thoroughly stirred. Ether (30 ml.) isadded and the precipitate filtered off, washed with ether and dried.Yield = 8.4 g.; M.P. = 227°-229° C.

b. 6-methylthio-2-Aminoquinoline-3-Carboxamide

A mixture of α-cyano-β-(2-nitro-5-methylthiophenyl)acrylamide (8.4 g.,0.032 mole) in acetic acid - N,N-dimethylformamide (110 ml. of 1:1) isheated in a 75° C. bath. Iron powder (2:0 g.) is added and the mixturestirred until the internal temperature rose to 95° C. Additional ironpowder (6.16 g. total iron added =0.146 mole) is added in small portionsover a fifteen-minute period. The reaction mixture is stirred for onehour following completion of addition and then filtered hot. The ironresidue is washed with hot acetic acid and the combined filtrate andwash solution poured into IN hydrochloric acid (200 ml.). Thehydrochloride salt which separates is filtered off and dissolved in hotdilute aqueous sodium hydroxide. The yellow solid which separates oncooling is filtered off, washed with isopropyl alcohol and air-dried.Yield = 3.26 g. (44%); M.P. 229°-242° C.

It is used in Step C without further purification.

C. ethyl 7-methylthiopyrimido [4,5-b]quinoline-4(3H)-one-2-carboxylate

A round-bottom flask equipped with stirrer, condenser, thermometer andDean-Stark trap and containing a mixture of6-methylthio-2-aminoquinoline-3-carboxamide (1.0 g., 4.3 millimoles),diethyl oxalate (20 ml.) and xylene (15 ml.) is immersed in an oil-bathheated to 200° C. Xylene, water and ethanol are distilled from thereaction mixture until the internal temperature of the mixture reaches165° C. The mixture is stirred at 165° C. for three hours and is thenpoured into chloroform (40 ml.). After cooling to room temperature themixture is filtered. The brown filter cake is air-dried and thenslurried in hot chloroform (100 ml.) to which activated charcoal isadded. The slurry is filtered hot and the filtrate evaporated tohalf-volume and chilled in ice. The yellow solid which precipitates isfiltered and dried in air; 142 mg. (11%). M.P. 240°- 242° C.

Analysis: Calcd. for C₁₅ H₁₃ O₃ S: C, 57.2; H, 4.16; N, 13.33% Found: C,56.72; H, 4.13; N, 13.22%.

EXAMPLE XXII Ethyl7-Methylsulfinylpyrimido[4,5-b]quinoline-4(3H)-One-2-Carboxylate

A solution of ethyl 7-methylthiopyrimido[4,5-b]quinoline-4(3H)-one-2-carboxylate (315 mg., 1 millimole) intrifluoroacetic acid (2 ml.) is heated in an oil bath to 55° C. Hydrogenperoxide (113 mg. of 30% H₂ O₂, 1 millimole) is added and the solutionstirred for ten minutes. After cooling to room temperature, absoluteethanol (6 ml.) is added. The resulting yellow precipitate is filteredoff, washed with ether and air-dried. Recrystallization from absoluteethanol gives 185 mg. (56%) of product; m.p. 257°- 259° C.

Analysis: Calcd. for C₁₅ H₁₃ N₃ O₄ S; C, 54.4; H, 3.97; N, 12.7% Found:C, 54.23; H, 3.97; N, 12.69%.

The thiomethyl compounds of Example XVIII are oxidized to thecorresponding sulfinylmethyl compounds by this procedure.

EXAMPLE XXIII

Repetition of the procedures of Examples V-A, XXI A-C and XXII, butusing the appropriate chloro substituted 2-nitrobenzaldehydes asreactants, affords the following compounds:

    ______________________________________                                         ##STR11##                                                                    R.sub.2   R.sub.3     R.sub.4  R.sub.5                                        ______________________________________                                        H         H           SOCH.sub.3                                                                             H                                              SOCH.sub.3                                                                              H           H        H                                              H         H           H        SOCH.sub.3                                     H         SOCH.sub.3  SOCH.sub.3                                                                             H                                              H         SOC.sub.7 H.sub.7                                                                         C.sub.2 H.sub.5                                                                        H                                              H         H           SOC.sub.7 H.sub.7                                                                      H                                              SOC.sub.7 H.sub.7                                                                       H           H        SOC.sub.7 H.sub.7                              ______________________________________                                    

example xxiv2-methyl-7-Hydroxy-8-Methoxypyrimido[4,5-b]Quinolin-4(3H)One

A. 7-Benzyl ether of title compound:

A mixture of 6-benzyloxy-7-methoxy-2-amino-quinoline-3-carboxamide (1.50g.), concentrated sulfuric acid (0.05 ml.) and acetic anhydride (20 ml.)is heated at 85° C. for 15 minutes. The mixture is then cooled and icechips added to the reaction mixture. The yellow which precipitates isfiltered, washed with water, and then with isopropyl alcohol-ether (1:1)and air-dried. Yield = 1.60 g. (99%); m.p. 202°- 203° C. (dec.).

B. Debenzylation of 7-benzyl ether.

The 7-benzyl ether from preparation A above is treated withtrifluoroacetic acid according to the procedure of Example XV to givethe title compound in 95% yield; m.p. 135° C. (dec.).

EXAMPLE XXV 2-Methyl-7,8-Dimethoxypyrimido [4,5-b]Quinolin-4(3H)-One

Concentrated sulfuric acid (1.5 ml.) is added to a slurry of6,7-dimethoxy-2-aminoquinoline-3-carboxamide (5.0 g., 0.02 mole) andacetic anhydride (40 ml). The slurry dissolves to give a dark orangesolution from which a heavy yellow precipitate separates. Aceticanhydride (10 ml.) is added to facilitate stirring and heating continuedfor an additional 75 minutes. The mixture is cooled, water (50 ml.)added and the resulting solution made alkaline with 5N sodium hydroxide(225 ml.). It is chilled, the precipitate collected by filtration andair-dried. The yellow solid is recrystallized from ethanol. Yield = 2.37g., M.P. 300° -302° (dec.).

In like manner, the following compounds are prepared from appropriatereactants:

    ______________________________________                                         ##STR12##                                                                    R.sub.1 R.sub.2   R.sub.3   R.sub.4 R.sub.5                                   ______________________________________                                        H       H         OCH.sub.3 OC.sub.2 H.sub.5                                                                      H                                         H       H         F         H       H                                         H       H         H         F       H                                         H       H         Cl        H       H                                         H       H         H         OCH.sub.3                                                                             H                                         H       H         H         H       OCH.sub.3                                 H       Cl        H         H       H                                         H       OCH.sub.3 H         H       OCH.sub.3                                 H       H         OCH.sub.2O      H                                           H       OCH.sub.3 OCH.sub.2O      H                                           H       H         t-C.sub.4 H.sub.9                                                                       H       H                                         H       H         OCH.sub.2CH.sub.2O                                                                            H                                           H       OCH.sub.3 OCH.sub.3 OCH.sub.3                                                                             H                                         H       H         OC.sub.2 H.sub.5                                                                        OC.sub.2 H.sub.5                                                                      H                                         H       H         CH.sub.3  CH.sub.3                                                                              H                                         H       Br        H         H       H                                         C.sub.6 H.sub.5                                                                       H         H         H       H                                         C.sub.6 H.sub.5                                                                       H         OCH.sub.3 OCH.sub.3                                                                             H                                         C.sub.6 H.sub.5                                                                       H         CH.sub.3  CH.sub.3                                                                              H                                         C.sub.6 H.sub.5                                                                       Cl        H         H       H                                         C.sub.6 H.sub.5                                                                       H         OCH.sub.2O      H                                           C.sub.6 H.sub.5                                                                        H        Cl        Br      Cl                                        C.sub.6 H.sub.5                                                                       H         t-C.sub.4 H.sub.9                                                                       H       H                                         CH.sub.3                                                                              H         H         H       H                                         CH.sub.3                                                                              H         H         OCH.sub.3                                                                             H                                         CH.sub.3                                                                              H         OCH.sub.3 OC.sub.2 H.sub.5                                                                      H                                         CH.sub.3                                                                              OCH.sub.3 H         H       OCH.sub.3                                 CH.sub.3                                                                              H         CH.sub.3  H       H                                         CH.sub.3                                                                              H         H         Cl      H                                         C.sub.2 H.sub.5                                                                       H         H         H       H                                         C.sub.2 H.sub.5                                                                       H         OCH.sub.3 OCH.sub.3                                                                             H                                         C.sub.2 H.sub.5                                                                       H         C.sub.2 H.sub.5                                                                         H       H                                         C.sub.2 H.sub.5                                                                       Cl        H         H       H                                         n-C.sub.3 H.sub.7                                                                     H         H         H       H                                         n-C.sub.3 H.sub.7                                                                     H         OCH.sub.3 OCH.sub.3                                                                             H                                         n-C.sub.4 H.sub.9                                                                     H         H         H       H                                         n-C.sub.4 H.sub.9                                                                     H         OCH.sub.3 OCH.sub.3                                                                             H                                         n-C.sub.4 H.sub.9                                                                     OCH.sub.3 H         H       OCH.sub.3                                 n-C.sub.4 H.sub.9                                                                     H         Cl        H       H                                         n-C.sub.4 H.sub.9                                                                     H         n-C.sub.3 H.sub.7                                                                       n-C.sub.3 H.sub.7                                                                     H                                         n-C.sub.4 H.sub.9                                                                     OCH.sub.3 OCH.sub.2O      H                                           n-C.sub.4 H.sub.9                                                                     H         SCH.sub.3 H       H                                         n-C.sub.4 H.sub.9                                                                     H         SOCH.sub.3                                                                              H       H                                         CH.sub.3                                                                              H         SCH.sub.3 H       H                                         CH.sub.3                                                                              H         SOCH.sub.3                                                                              H       H                                         H       H         SCH.sub.3 H       H                                         H       H         SOCH.sub.3                                                                              H       H                                         H       H         SCH.sub.3 SCH.sub.3                                                                             H                                         H       H         SOCH.sub.3                                                                              SOCH.sub.3                                                                            H                                         C.sub.6 H.sub.5                                                                       H         SCH.sub.3 H       H                                         C.sub.6 H.sub.5                                                                       H         SOCH.sub.3                                                                              H       H                                         C.sub.6 H.sub.5                                                                       H         OCH.sub.3 OC.sub.7 H.sub.7                                                                      H                                         CH.sub.3                                                                              CH.sub.3  CH.sub.3  CH.sub.3                                                                              OCH.sub.3                                 CH.sub.3                                                                              H         OCH.sub.3 H       H                                         H       H         OCH.sub.3 OC.sub.7 H.sub.7                                                                      H                                         H       H         OC.sub.7 H.sub.7                                                                        OCH.sub.3                                                                             H                                         H       H         SC.sub.7 H.sub.7                                                                        H       H                                         H       H         H         OC.sub.7 H.sub.7                                                                      OCH.sub.3                                 H       H         H         OC.sub.7 H.sub.7                                                                      H                                         H       OC.sub.7 H.sub.7                                                                        OCH.sub.3 H       H                                         H       OC.sub.7 H.sub.7                                                                        H         H       H                                         H       OC.sub.7 H.sub.7                                                                        Br        H       Br                                        H       H         OCH.sub.3 OC.sub.7 H.sub.7                                                                      Br                                        H       C.sub.2 H.sub.5                                                                         H         OC.sub.7 H.sub.7                                                                      H                                         H       C.sub.2 H.sub.5                                                                         OC.sub.7 H.sub.7                                                                        H       H                                         H       H         SC.sub.7 H.sub.7                                                                        OC.sub.2 H.sub.5                                                                      H                                         H       H         OC.sub.2 H.sub.5                                                                        SC.sub.7 H.sub.7                                                                      H                                         H       H         Br        SC.sub.7 H.sub.7                                                                      H                                         H       H         Cl        OC.sub.7 H.sub.7                                                                      H                                         H       H         F         OC.sub.7 H.sub.7                                                                      H                                         C.sub.6 H.sub.5                                                                       OC.sub.7 H.sub.7                                                                        OCH.sub.3 OCH.sub.3                                                                             H                                         C.sub.6 H.sub.5                                                                       H         OCH.sub.3 OC.sub.7 H.sub.7                                                                      H                                         C.sub.6 H.sub.5                                                                       H         OC.sub.7 H.sub.7                                                                        OCH.sub.3                                                                             H                                         C.sub.6 H.sub.5                                                                       H         SC.sub.7 H.sub.7                                                                        H       H                                         C.sub.6 H.sub.5                                                                       H         H         OC.sub.7 H.sub.7                                                                      OCH.sub.3                                 C.sub.6 H.sub.5                                                                       H         Cl        OC.sub.7 H.sub.7                                                                      H                                         CH.sub.3                                                                              H         OC.sub.7 H.sub.7                                                                        OCH.sub.3                                                                             H                                         CH.sub.3                                                                              H         SC.sub.7 H.sub.7                                                                        OC.sub.2 H.sub.5                                                                      H                                         CH.sub.3                                                                              H         F         OC.sub.7 H.sub.7                                                                      H                                         C.sub.2 H.sub.5                                                                       H         OC.sub.7 H.sub.7                                                                        H       H                                         n-C.sub.3 H.sub.7                                                                     H         OC.sub.7 H.sub.7                                                                        OCH.sub.3                                                                             H                                         n-C.sub.4 H.sub.9                                                                     H         OC.sub.7 H.sub.7                                                                        OCH.sub.3                                                                             H                                         n-C.sub.4 H.sub.7                                                                     C.sub.2 H.sub.5                                                                         SC.sub.7 H.sub.7                                                                        H       H                                         n-C.sub.4 H.sub.9                                                                     OC.sub.7 H.sub.7                                                                        OCH.sub.3 OCH.sub.3                                                                             H                                         ______________________________________                                    

the benzyl ethers and benzylthio ethers enumerated above aredebenzylated by treatment with trifluoroacetic acid as is described inExample XV.

EXAMPLE XXVI 2-Ethyl-7,8-Dimethoxypyrimidin [4,5-b]quinolin-4(3H)-One

To a stirred mixture of 6,7-dimethoxy-2-aminoquinoline-3-carboxamide(500 mg., 0.002 mole) in propionic anhydride (10 ml.) at 60° C. is addedconcentrated sulfuric acid (0.5 ml.). The reaction mixture is stirredfor one hour and is then cooled to room temperature and added to water(25 ml.). The aqueous mixture is stirred and made basic with 6N sodiumhydroxide. It is stirred overnight and then acidified to pH 5.0 with 10%hydrochloric acid. The yellow precipitate which forms is filtered offand recrystallized from ethanol. Yield = 283 mg., M.P. 290°-291° C.(dec.). A second crop of product separates on standing. The two cropsare combined and recrystallize from chloroform: ethanol (1:1). Yield =225 mg. (39%); M.P. 293° C.

The following compounds are prepared in like manner from appropriatereactants:

    ______________________________________                                         ##STR13##                                                                    R.sub.1                                                                              R.sub.2 R.sub.3      R.sub.4    R.sub.5                                ______________________________________                                        H      H       H            H          H                                      H      OCH.sub.3                                                                             H            H          H                                      H      H       OCH.sub.3    H          H                                      H      H       H            OC.sub.2 H.sub.5                                                                         H                                      H      H       OCH.sub.3    OC.sub.2 H.sub.5                                                                         H                                      H      H       OC.sub.2 H.sub.5                                                                           OC.sub.2 H.sub.5                                                                         H                                      H      H       OC.sub.2 H.sub.5                                                                           OCH.sub.3  H                                      H      H       OC.sub.2 H.sub.5                                                                           O-(n-C.sub.4 H.sub.9)                                                                    H                                      H      H       OC.sub.2 H.sub.5                                                                           OC.sub.7 H.sub.7                                                                         H                                      H      H       H            OCH.sub.3  OCH.sub.3                              H      H       H            OCH.sub.3  H                                      H      OCH.sub.3                                                                             H            H          OCH.sub.3                              H      H       OCH.sub.3    H          OCH.sub.3                              H      H       SCH.sub.3    H          H                                      H      H       SOCH.sub.3   H          H                                      H      H       OCH.sub.3    OCH.sub.3  OCH.sub.3                              H      H       H            F          H                                      H      H       F            H          H                                      H      H       Cl           H          H                                      H      Cl      H            H          H                                      H      H       OCH.sub.2 O           H                                        H      H       OCH.sub.2 CH.sub.2 O  H                                        H      OCH.sub.3                                                                             OCH.sub.2 O           H                                        H      H       CH.sub.3     CH.sub.3   H                                      H      H       C.sub.2 H.sub.5                                                                            H          H                                      H      H       t-C.sub.4 H.sub.9                                                                          H          H                                      H      H       CH.sub.3     H          H                                      H      H       n-C.sub.3 H.sub.7                                                                          n-C.sub.3 H.sub.7                                                                        H                                      H      Br      H            H          H                                      H      H       Cl           Br         Cl                                     H      H       H            I          H                                      C.sub.6 H.sub.5                                                                      H       H            H          H                                      C.sub.6 H.sub.5                                                                      H       OCH.sub.3    OCH.sub.3  H                                      C.sub.6 H.sub.5                                                                      H       CH.sub.3     CH.sub.3   H                                      C.sub.6 H.sub.5                                                                      Cl      H            H          H                                      C.sub.6 H.sub.5                                                                      H       OCH.sub.2 O           H                                        C.sub.6 H.sub.5                                                                      H       t-C.sub.4 H.sub.9                                                                          H          H                                      CH.sub.3                                                                             H       OCH.sub.3    OC.sub.2 H.sub.5                                                                         H                                      CH.sub.3                                                                             H       CH.sub.3     H          H                                      CH.sub.3                                                                             H       H            Cl         H                                      C.sub.2 H.sub.5                                                                      H       H            H          H                                      C.sub.2 H.sub.5                                                                      H       OCH.sub.3    OCH.sub.3  H                                      C.sub.2 H.sub.5                                                                      H       n-C.sub.3 H.sub.7                                                                          H          H                                      C.sub.2 H.sub.5                                                                      OCH.sub.2 O      OCH.sub.3    H                                        C.sub.2 H.sub.5                                                                      Br      H            H          H                                      n-C.sub.3 H.sub.7                                                                    H       OCH.sub.2 CH.sub.2 O  H                                        n-C.sub.3 H.sub.7                                                                    H       H            OC.sub.2 H.sub.5                                                                         H                                      n-C.sub.4 H.sub.9                                                                    H       OCH.sub.3    OCH.sub.3  H                                      n-C.sub.4 H.sub.9                                                                    H       H            i-C.sub.3 H.sub.7                                                                        H                                      n-C.sub.4 H.sub.9                                                                    H       SCH.sub.3    H          H                                      n-C.sub.4 H.sub.9                                                                    H       SOCH.sub.3   H          H                                      CH.sub.3                                                                             H       O-(n-C.sub. 4 H.sub.9)                                                                     O-(n-C.sub. 4 H.sub.9)                                                                   H                                      C.sub.6 H.sub.5                                                                      H       SCH.sub.3    SCH.sub.3  H                                      C.sub.6 H.sub.5                                                                      H       SOCH.sub.3   SOCH.sub.3 H                                      H      H       OCH.sub.3    OC.sub.7 H.sub.7                                                                         H                                      H      H       OC.sub.7 H.sub.7                                                                           OCH.sub.3  H                                      H      H       OC.sub.7 H.sub.7                                                                           H          H                                      H      H       F            OC.sub.7 H.sub.7                                                                         H                                      H      H       Cl           OC.sub.7 H.sub.7                                                                         H                                      H      C.sub.2 H.sub.5                                                                       H            OC.sub.7 H.sub.7                                                                         H                                      H      OC.sub.7 H.sub.7                                                                      OCH.sub.3    OCH.sub.3  H                                      C.sub.6 H.sub.5                                                                      H       OC.sub.7 H.sub.7                                                                           OCH.sub.3  H                                      C.sub.6 H.sub.5                                                                      H       OC.sub.7 H.sub.7                                                                           H          H                                      C.sub.6 H.sub.5                                                                      OC.sub.7 H.sub.7                                                                      Br           H          Br                                     CH.sub.3                                                                             H       OC.sub.7 H.sub.7                                                                           OCH.sub.3  H                                      CH.sub.3                                                                             H       OCH.sub.3    OC.sub.7 H.sub.7                                                                         H                                      CH.sub.3                                                                             H       OC.sub.7 H.sub.7                                                                           OC.sub.2 H.sub.5                                                                         H                                      CH.sub.3                                                                             H       OCH.sub.3    OC.sub.7 H.sub.7                                                                         Br                                     C.sub.2 H.sub.5                                                                      H       F            OC.sub.7 H.sub.7                                                                         H                                      C.sub.2 H.sub.5                                                                      H       OC.sub.7 H.sub.7                                                                           OCH.sub.3  H                                      C.sub.2 H.sub.5                                                                      OC.sub.7 H.sub.7                                                                      OCH.sub.3    H          H                                      n-C.sub.3 H.sub.7                                                                    H       OC.sub.2 H.sub.7                                                                           OC.sub.2 H.sub.5                                                                         H                                      i-C.sub.3 H.sub.7                                                                    H       OC.sub.7 H.sub.7                                                                           OC.sub.2 H.sub.5                                                                         H                                      n-C.sub.4 H.sub.9                                                                    H       OC.sub.7 H.sub.7                                                                           H          H                                      n-C.sub.4 H.sub.9                                                                    C.sub.2 H.sub.5                                                                       OC.sub.7 H.sub.7                                                                           H          H                                      n-C.sub.4 H.sub.9                                                                    H       OC.sub. 7 H.sub.7                                                                          OCH.sub.3  H                                      ______________________________________                                    

debenzylation of the benzyl ethers cited above by reaction withtrifluoroacetic acid according to the procedure of Example XV affordsthe corresponding hydroxy compounds.

EXAMPLE XXV 2-Acetyl-7,8-Dimethoxypyrimido[4,5-b]quinoline-4(3H)-One

To a solution of selenium dioxide-(24.5 mg., 2.2 millimoles) in dioxanewater (11 ml. of 10:1) is added 2-ethyl-7,8-dimethoxypyrimido)[4,5-quinolin-4(3H)-one (125 mg., 4.4 millimoles). The mixture is heatedto reflux for 48 hours after which more selenium dioxide (24.5 mg.) isadded and refluxing continued for an additional 24 hours. The mixture iscooled, the selenium filtered off and the filtrate concentrated todryness. The residue is taken up in ethanol/chloroform (1:99) andchromatographed on a column of silica using the same solvent as eluant(250 ml.) followed by ethanol/chloroform (2.98). Concentration of thesecond eluate (625 ml.) gives a yellow solid (23 mg.); M.P. 300° C(dec.).

Similarly, the remaining 2-ethyl derivatives of Example XXVI areoxidized to their corresponding 2-acetyl derivatives.

EXAMPLE XXVIII Ethyl 5-Phenylpyrimido[4,5-b]Quinolin-4(3H)-One-2-Carboxylate

A mixture of 2-amino-4-phenylquinoline-3-carboxamide (263 mg., 1.0millimole), diethyl oxalate (5 ml.) acetic acid (5 ml.) is heated toreflux overnight. It is then cooled, diluted with ether (50 ml.) and thebrown solid which forms filtered off. The filtrate is evaporated invacuo and the oily residue triturated with saturated aqueous sodiumbicarbonate solution. The resulting solid (110 mg.) is recovered byfiltration and recrystallized from hot ethyl acetate (8 ml.). A smallamount of insoluble material is filtered off from the hot solution. Uponcooling, the title product separates as crystals (25 mg.). M.P. = 255°C. (dec.).

Analysis: Calcd. for C₂₀ H₁₅ N₃ O₃ : C, 69.55; H, 4.38; N, 12.17%Found*: C, 69.94; H, 4.31; N, 12.17%.

In like manner, the 2-amino-4-substituted-quinoline-3-carboxamides ofPreparation D are converted to ethyl5-substituted-pyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylates of theformula ##STR14## wherein the R variables have the values given inPreparation D.

The esters thus obtained are transformed to the corresponding amide andhydroxamic acid derivatives by the procedures of Examples VII and XIV,respectively.

EXAMPLE XXIX Ethyl3-Methyl-7,8-Dimethoxypyrimido[4,5-b]quinolin-4(3H)-One-2-Carboxylate

Sodium hydride (470 mg. of 50% in oil, 0.011 mole) is added to a slurryof ethyl 7,8-dimethoxypyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate(3.3 g., 0.01 mole) in N,N-dimethylformamide (75 ml.). The mixture isstirred and heated on a steambath for ten minutes and then at roomtemperature for a half hour. It is cooled in an ice-bath and iodomethane(2.1 g., 0.015 mole) added dropwise over a 30 minute period. Followingcompletion of addition, the mixture is stirred for an additional 15minutes in an ice-bath and then for a half-hour at room temperature. Thereaction mixture is poured into ice-water (200 ml.) and the resultingsolid filtered off, air-dried, and recrystallized from ethanol to give2.1 g. of yellow crystals (61.2%); m.p. 211.5° C. (dec.)

Analysis: Calcd. for C₁₇ H₁₇ N₃ O₅ : C, 59.47; H, 4.99; N, 12.24% Found:C, 59.55; H, 5.02; N, 12.45%.

In like manner, but using the appropriate compound of formula I (Y═H)and the appropriate alkyl iodide, the products of Examples I andIII-XXVIII are converted to their corresponding 3-methyl, 3-ethyl,3-n-propyl, 3-isopropyl and 3-n-butyl derivatives.

Compounds wherein one of R₂, R₃, R₄, or R₅ is thiol or hydroxy areobtained by debenzylation of the corresponding benzylthio ethers orbenzylethers by reaction with trifluoroacetic acid according to theprocedure of Example XV.

EXAMPLE XXX Ethyl3-Carbethoxymethyl-7,8-Dimethoxypyrimido[4,5-b]quinolin-4(3H)-One-2-Carboxylate

To a slurry of ethyl7,8-dimethoxypyrimido[4,5-b]quinolin-4-(3H)-one-2-carboxylate (1.6 g.,5.0 millimoles) in N,N-dimethylformamide (30 ml.) is added sodiumhydride (235 mg., 5.5 millimoles of 56% in oil). The slurry is heated ona steambath for ten minutes and then cooled to room temperature. Ethylbromoacetate (968 mg., 5.8 millimoles) is added and the reaction mixtureheated on a steambath for one hour. After standing overnight at roomtemperature the mixture is diluted with water (75 ml.) and the resultingyellow solid filtered off (1.4 g.). It is purified by chromatography ona column of silica gel using chloroform as solvent and eluant. Theeluate (300 ml.) is evaporated to give 1.2 g. of yellow solid. It isrecrystallized from hot ethanol (50 ml.) containing sufficientchloroform to achieve solution. Yield = 900 mg. of fluffy yellowcrystals (43.4%); m.p. 198°-199° C. (dec.)

Analysis: Calcd. for C₂₀ H₂₁ N₃ O₇ : C, 57.83; H, 5.10; N, 10.12% Found:C, 59.67; H, 4.99; N, 9.90%.

EXAMPLE XXXI Ethyl3-(3-Carbethoxypropyl)-7,8-Dimethoxypyrimido[4,5-b]quinolin-4(3H)-One-2-Carboxylate

The procedure of Example XXX is repeated but using ethyl 4-bromobutyrate(1.1 g., 5.8 millimole) in place of ethyl bromoacetate. The solidobtained upon diluting the reaction mixture with water is filtered off,dried and recrystallized from benzene: hexane (40 ml. of 1:1) to give615 mg. (29.1%) of the title compound as fluffy yellow crystals; M.P.144°-146° C.

Analysis: Calcd. for C₂₂ H₂₅ N₃ O₇ : C, 59.58; H, 5.68; N, 9.48% Found:C, 59.84; H, 5.98, H, 9.61%.

EXAMPLE XXXII

Pyrimido [4,5-b]quinolin-4(3H)-one compounds of Examples I-XXVIII arealkylated substantially according to the procedure of Example XXXI butusing the appropriate alkyl bromoalkanoate in place of ethyl 4-bromobutyrate. The products are recrystallized from suitable solvents such asethanol or benzene: hexane (1:1).

    __________________________________________________________________________     ##STR15##                                                                    Y           R         R.sub.1                                                                            R.sub.2                                                                              R.sub.3                                                                              R.sub.4                                                                              R.sub.5                       __________________________________________________________________________    CH.sub.2 COOCH.sub.3                                                                      COOC.sub.2 H.sub.5                                                                      H    H      H      H      H                             CH.sub.2 COO-n-C.sub.4 H.sub.9                                                            COOC.sub.2 H.sub.5                                                                      H    H      H      H      H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               COO-n-C.sub.4 H.sub.9                                                                   H    H      OCH.sub.3                                                                            OCH.sub.3                                                                            H                             CH.sub.2 COO-n-C.sub.3 H.sub.7                                                            COOC.sub.2 H.sub.5                                                                      H    H      OCH    H      OCH.sub.3                     CH.sub.2 CH.sub.2 COOCH.sub.3                                                             COOC.sub.2 H.sub.5                                                                      H    OCH.sub.3                                                                            H      H      OCH.sub.3                     CH.sub.2 CH.sub.2 COO-n-C.sub.3 H.sub.7                                                   COOC.sub.2 H.sub.5                                                                      H    H      OCH.sub.3                                                                            OCH.sub.3                                                                            H                             (CH.sub.2).sub.4 COOC.sub.2 H.sub.5                                                       COOC.sub.2 H.sub.5                                                                      H    H      OCH.sub.3                                                                            OCH.sub. 3                                                                           OCH.sub.3                     (CH.sub.2).sub.4 COO-n-C.sub.4 H.sub.9                                                    COOC.sub.2 H.sub.5                                                                      H    H      OC.sub.2 H.sub.5                                                                     O-n-C.sub.4 H.sub.9                                                                  H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               COOC.sub.2 H.sub.5                                                                      H    H      OC.sub.2 H.sub.5                                                                     OC.sub.7 H.sub.7                                                                     H                             (CH.sub.2).sub.3 COOCH.sub.3                                                              COOC.sub.2 H.sub.5                                                                      H    OC.sub.2 H.sub.5                                                                     OC.sub.2 H.sub.5                                                                     H      H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               COOC.sub.2 H.sub.5                                                                      H    H      OCH.sub.2 CH.sub.2 O                                                                        H                             CH.sub.2 COOCH.sub.3                                                                      COOC.sub.2 H.sub.5                                                                      H    H      F      H      H                             CH.sub.2 CH.sub.2 COOC.sub.2 H.sub.5                                                      COOC.sub.2 H.sub.5                                                                      H    H      H      F      H                             CH.sub.2 COO-i-C.sub.3 H.sub.7                                                            COOC.sub.2 H.sub.5                                                                      H    H      Cl     H      H                             CH.sub.2 CH.sub.2 COOCH.sub.3                                                             COOC.sub.2 H.sub.5                                                                      H    H      OCH.sub.2O    H                             CH.sub.2 COOCH.sub.3                                                                      Coo-n-C.sub.4 H.sub.9                                                                   H    H      H      H      H                             CH.sub.2 CH.sub.2 COOCH.sub.3                                                             COOC.sub.2 H.sub.5                                                                      H    Cl     H      H      H                             CH.sub.2 COO-i-C.sub.3 H.sub.7                                                            COOC.sub.2 H.sub.5                                                                      H    H      H      OCH.sub.3                                                                            OCH.sub.3                     CH.sub.2 COOC.sub.2 H.sub.5                                                               COOCH.sub.2 CH.sub.2 OH                                                                 H    H      OCH.sub.3                                                                            OCH.sub.3                                                                            H                             (CH.sub.2).sub.3 COOCH.sub.3                                                              COOC.sub.2 H.sub.5                                                                      H    H      O-n-C.sub.4 H.sub.9                                                                  O-n-C.sub.4 H.sub.9                                                                  H                             CH.sub.2 CH.sub.2 COOCH.sub.3                                                             COOC.sub.2 H.sub.5                                                                      H    OCH.sub.3                                                                            OCH.sub.2O    H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               COOC.sub.2 H.sub.5                                                                      H    H      Br     H      Br                            (CH.sub.2).sub.4 COOC.sub.2 H.sub.5                                                       COOC.sub.2 H.sub.5                                                                      H    Cl     H      H      Cl                            (CH.sub.2).sub.3 COO-n-C.sub.3 H.sub.7                                                    COO-i-C.sub.3 H.sub.7                                                                   H    H      CH.sub.3                                                                             H      H                             CH.sub.2 CH.sub.2 COOC.sub.2 H.sub.5                                                      COOC.sub.2 H.sub.5                                                                      H    H      H      CH.sub.3                                                                             H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               COOC.sub.2 H.sub.5                                                                      H    H      t-C.sub.4 H.sub.9                                                                    H      H                             CH.sub.2 COOCH.sub.3                                                                      COOCH.sub.3                                                                             H    CH.sub.3                                                                             H      CH.sub.3                                                                             H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               COOC.sub.2 H.sub.5                                                                      H    H      n-C.sub.3 H.sub.7                                                                    H      H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               COOC.sub.2 H.sub.5                                                                      H    H      SCH.sub.3                                                                            H      H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               COOC.sub.2 H.sub.5                                                                      C.sub.6 H.sub.5                                                                    H      H      H      H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               COOC.sub.2 H.sub.5                                                                      C.sub.6 H.sub.5                                                                    H      OCH.sub.3                                                                            OCH.sub.3                                                                            H                             (CH.sub.2).sub.3 COOCH.sub.3                                                              COOC.sub.2 H.sub.5                                                                      CH.sub.3                                                                           H      OCH.sub.3                                                                            OCH.sub.3                                                                            H                             (CH.sub.2).sub.4 COOC.sub.2 H.sub.5                                                       COOC.sub.2 H.sub.5                                                                      CH.sub.3                                                                           H      H      OC.sub.2 H.sub.5                                                                     OC.sub.2 H.sub.5              CH.sub.2 COO-n-C.sub.4 H.sub.9                                                            COOC.sub.2 H.sub.5                                                                      CH.sub.3                                                                           H      CH.sub.3                                                                             CH.sub.3                                                                             H                             CH.sub.2 CH.sub.2 COOC.sub.2 H.sub.5                                                      COOC.sub.2 H.sub.5                                                                      n-C.sub.3 H.sub.7                                                                  H      Cl     H      H                             CH.sub.2 COO-n-C.sub.3 H.sub.7                                                            COOC.sub.2 H.sub.5                                                                      CH.sub.3                                                                           H      Cl     CH.sub.3                                                                             H                             CH.sub.2 COOn-C.sub.4 H.sub.9                                                             COOC.sub.2 H.sub.5                                                                      n-C.sub.4 H.sub.9                                                                  H      H      H      H                             (CH.sub.2).sub.3 COOC.sub.2 H.sub.5                                                       COOC.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                    H      Br     H      H                             CH.sub.2 COOCH.sub.3                                                                      COOC.sub.2 H.sub.5                                                                      C.sub.6 H.sub.5                                                                    H      F      H      H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               COOC.sub.2 H.sub.5                                                                      CH.sub.3                                                                           H      OCH.sub.2 CH.sub.2O                                                                         H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               COOC.sub.2 H.sub.5                                                                      C.sub.6 H.sub.5                                                                    H      OCH.sub.2O    H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               COOCH.sub.2 CH.sub.2 OH                                                                 H    H      OCH.sub.3                                                                            OCH.sub.3                                                                            H                             CH.sub.3 COOC.sub.2 H.sub.5                                                               COO(CH.sub.2).sub.3 OH                                                                  H    H      OC.sub.2 H.sub.5                                                                     OCH.sub.3                                                                            H                             CH.sub.2 COOCH.sub.3                                                                      COO(CH.sub.2).sub.4 OH                                                                  H    H      H      H      H                             CH.sub.2 COOCH.sub.2 CH.sub.2 OH                                                          COOCH.sub.2 CH.sub.2 OH                                                                 H    H      OCH.sub.3                                                                            OCH.sub.3                                                                            H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               CH.sub.3  H    H      OCH.sub.3                                                                            OCH.sub.3                                                                            H                             (CH.sub.2).sub. 3 COOC.sub.2 H.sub.5                                                      CH.sub.3  H    Cl     H      H      H                             CH.sub.2 COOCH.sub.3                                                                      CH.sub.3  H    H      F      H      H                             (CH.sub.2).sub.2 COOC.sub.2 H.sub.5                                                       CH.sub.3  H    H      OCH.sub.2O    H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               CH.sub.3  H    H      t-C.sub.4 H.sub.9                                                                    H      H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               CH.sub.3  C.sub.6 H.sub.5                                                                    H      SCH.sub.3                                                                            H      H                             CH.sub.2 CH.sub.2 COOCH.sub.3                                                             C.sub.2 H.sub.5                                                                         H    H      OCH.sub.3                                                                            OCH.sub.3                                                                            H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               C.sub.2 H.sub.5                                                                         CH.sub.3                                                                           H      Cl     Br     Cl                            CH.sub.2 COOC.sub.2 H.sub.5                                                               C.sub.2 H.sub.5                                                                         n-C.sub.4 H.sub.9                                                                  H      SOCH.sub.3                                                                           H      H                             CH.sub.2 COOCH.sub.3                                                                      COCH.sub.3                                                                              H    H      OCH.sub.3                                                                            OCH.sub.3                                                                            H                             (CH.sub.2).sub.2 COOCH.sub.3                                                              COCH.sub.3                                                                              H    Cl     H      H      H                             (CH.sub.2).sub.2 COOCH.sub.3                                                              COCH.sub.3                                                                              C.sub.6 H.sub.5                                                                    H      CH.sub.3                                                                             H      H                             (CH.sub.2).sub.3 COOC.sub.2 H.sub.5                                                       COCH.sub.3                                                                              C.sub.2 H.sub.5                                                                    H      H      H      H                             CH.sub.2 COOCH.sub.3                                                                      COOC.sub.2 H.sub.5                                                                      H    H      OC.sub.7 H.sub.7                                                                     OCH.sub.3                                                                            H                             (CH.sub.2).sub.2 COOC.sub.2 H.sub.5                                                       COO-n-C.sub.4 H.sub.9                                                                   H    H      OC.sub.7 H.sub.7                                                                     OCH.sub.3                                                                            H                             CH.sub.2 COO-n-C.sub.4 H.sub.9                                                            COOC.sub.2 H.sub.5                                                                      H    H      OC.sub.7 H.sub.7                                                                     H      H                             (CH.sub.2).sub.3 COOC.sub.2 H.sub.5                                                       COOC.sub.2 H.sub.5                                                                      H    H      OCH.sub.3                                                                            OC.sub.7 H.sub.7                                                                     H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               COOCH.sub.3                                                                             H    H      OC.sub.7 H.sub.7                                                                     OC.sub.7 H.sub.7                                                                     H                             (CH.sub.2).sub.4 COOCH.sub.3                                                              COOC.sub.2 H.sub.5                                                                      H    OC.sub.7 H.sub.7                                                                     OCH.sub.3                                                                            OCH.sub.3                                                                            H                             (CH.sub.2).sub.2 COO-n-C.sub.4 H.sub.9                                                    COO-n-C.sub.4 H.sub.9                                                                   H    H      H      H      OC.sub.7 H.sub.7              CH.sub.2 COO-n-C.sub.3 H.sub.7                                                            COO-n-C.sub.3 H.sub.7                                                                   H    C.sub.2 H.sub.5                                                                      OC.sub.7 H.sub.7                                                                     H      H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               COOC.sub.2 H.sub.5                                                                      H    H      Br     OC.sub.7 H.sub.7                                                                     H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               COOCH.sub.3                                                                             H    H      Cl     OC.sub.7 H.sub.7                                                                     H                             CH.sub.2 COOCH.sub.3                                                                      COOCH.sub.2 CH.sub.2 OH                                                                 H    H      OC.sub.7 H.sub.7                                                                     OCH.sub.3                                                                            H                             CH.sub.2 COOCH.sub.3                                                                      COOCH.sub.2 CH.sub.2 OH                                                                 H    H      OCH.sub.3                                                                            OC.sub.7 H.sub.7                                                                     H                             (CH.sub.2).sub.2 COOC.sub.2 H.sub.5                                                       COO(CH.sub.2).sub.4 OH                                                                  H    H      OC.sub.7 H.sub.7                                                                     H      H                             CH.sub.2 COO-n-C.sub.4 H.sub.9                                                            COO(CH.sub.2).sub.3 OH                                                                  H    H      F      OC.sub.7 H.sub.7                                                                     H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               CH.sub.3  H    H      OC.sub.7 H.sub.7                                                                     OCH.sub.3                                                                            H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               CH.sub.3  H    H      OC.sub.2 H.sub.5                                                                     OC.sub.7 H.sub.7                                                                     H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               CH.sub.3  H    OC.sub.7 H.sub.7                                                                     OCH.sub.3                                                                            H      H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               C.sub.2 H.sub.5                                                                         H    H      OC.sub.7 H.sub.7                                                                     H      H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               C.sub.2 H.sub.5                                                                         H    H      OCH.sub.3                                                                            OC.sub.7 H.sub.7                                                                     Br                            CH.sub.2 COOC.sub.2 H.sub.5                                                               C.sub.2 H.sub.5                                                                         H    H      Br     OC.sub.7 H.sub.7                                                                     H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               COCH.sub.3                                                                              H    H      OC.sub.7 H.sub.7                                                                     OCH.sub.3                                                                            H                             CH.sub.2 COOC.sub.2 H.sub. 5                                                              COCH.sub.3                                                                              H    C.sub.2 H.sub.5                                                                      H      OC.sub.7 H.sub.7                                                                     H                             CH.sub.2 COOCH.sub.3                                                                      CH.sub.3  C.sub.6 H.sub.5                                                                    H      OC.sub.7 H.sub.7                                                                     OCH.sub.3                                                                            H                             (CH.sub.2).sub.3 COOC.sub.2 H.sub.5                                                       C.sub.2 H.sub.5                                                                         C.sub.2 H.sub.5                                                                    OC.sub.7 H.sub.7                                                                     OCH.sub.3                                                                            H      H                             (CH.sub.2).sub.2 COO-n-C.sub.4 H.sub.9                                                    CH.sub.3  n-C.sub.4 H.sub.9                                                                  C.sub.2 H.sub.5                                                                      OC.sub.7 H.sub.7                                                                     H      H                             CH.sub.2 COOC.sub.2 H.sub.5                                                               CH.sub.3  CH.sub.3                                                                           H      OC.sub.7 H.sub.7                                                                     OCH.sub.3                                                                            H                             CH.sub.2 COOCH.sub.3                                                                      COOC.sub.2 H.sub.5                                                                      H    H      SC.sub.7 H.sub.7                                                                     H      H                             (CH.sub.2).sub.4 COOC.sub.2 H.sub.5                                                       COOC.sub.2 H.sub.5                                                                      H    H      H      H      SC.sub.7 H.sub.7              CH.sub.2 COOC.sub.2 H.sub.5                                                               COOC.sub.2 H.sub.5                                                                      H    H      SC.sub.7 H.sub.7                                                                     C.sub.2 H.sub.5                                                                      H                             (CH.sub.2).sub.2 COO-n-C.sub.4 H.sub.9                                                    COOC.sub.2 H.sub.5                                                                      H    H      H      SC.sub.7 H.sub.7                                                                     H                             CH.sub.2 COOCH.sub.3                                                                      COOC.sub.2 H.sub.5                                                                      H    SC.sub.7 H.sub.7                                                                     H      H      SC.sub.7 H.sub.7              CH.sub.2 COOCH.sub.3                                                                      COOC.sub.2 H.sub. 5                                                                     H    SOC.sub.7 H.sub.7                                                                    H      H      H                             (CH.sub.2).sub.3 COO-i-C.sub.3 H.sub.7                                                    COOC.sub.2 H.sub.5                                                                      H    H      SOC.sub.7 H.sub.7                                                                    C.sub.2 H.sub.5                                                                      H                             CH.sub.2 CH.sub.2 COOC.sub.2 H.sub.5                                                      COOC.sub.2 H.sub.5                                                                      H    H      SOC.sub.7 H.sub.7                                                                    H      H                             CH.sub.2 COOCH.sub.3                                                                      COOC.sub.2 H.sub.5                                                                      H    H      CH.sub.3 COO                                                                         OCH.sub.3                                                                            H                             (CH.sub.2).sub.4 COOC.sub.2 H.sub.5                                                       COOC.sub.2 H.sub.5                                                                      H    H      OCH.sub.3                                                                            C.sub.6 H.sub.5 COO                                                                  H                             __________________________________________________________________________

the benzyl ethers and benzylthio ethers tabulated above are converted tothe corresponding hydroxy and thiol compounds by reaction withtrifluoroacetic acid according to the procedure of Example XV.

EXAMPLE XXXIII Ethyl3-Acetoxyethyl-7,8-Dimethoxypyrimidin[4,5-b]quinolin-4(3H)-One-2-Carboxylate

The procedure of Example XXX is repeated but using bromoethyl acetate(969 mg., 5.8 millimoles) as alkylating agent in place of ethylbromoacetate. The solid product which separates upon dilution of thereaction mixture with water is filtered off, dried and recrystallizedfrom ethanol (20 ml.) containing sufficient acetonitrile to achievesolution. Yield = 550 mg. (26.5%); M.P. 195°-196° C. (dec.)

Analysis: Calcd. C₂₀ H₂₁ N₃ O₇ : C, 57.83; H, 5.10; N, 10.12% Found: C,57.95; H, 51.14; N, 10.31%.

In like manner, the following compounds are prepared from theappropriate pyrimidin[4,5-b]quinolin-4(3H)-one compounds of ExamplesI-XXVIII and the appropriate bromoalkanoate or bromoalkyl benzoate:

    __________________________________________________________________________     ##STR16##                                                                    Y         R        R.sub.1                                                                           R.sub.2                                                                           R.sub.3                                                                             R.sub.4                                                                             R.sub.5                                __________________________________________________________________________    CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           COOC.sub.2 H.sub.5                                                                     H   H   OC.sub.2 H.sub.5                                                                    H     H                                      CH.sub.2 CH.sub.2 OCOC.sub.2 H.sub.5                                                    COOC.sub.2 H.sub.5                                                                     H   H   H     OCH.sub.3                                                                           H                                      CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           COOC.sub.2 H.sub.5                                                                     H   H   OCH.sub.2O  H                                      (CH.sub.2).sub.3 OCOCH.sub.3                                                            COOC.sub.2 H.sub.5                                                                     H   H   OC.sub.2 H.sub.5                                                                    OC.sub.7 H.sub.7                                                                    H                                      (CH.sub.2).sub.4 OCOC.sub.2 H.sub.5                                                     COOC.sub.2 H.sub.5                                                                     H   OCH.sub.3                                                                         H     H     OCH.sub.3                              CH.sub.2 CH.sub.2 OCOC.sub.6 H.sub.5                                                    COOC.sub.2 H.sub.5                                                                     H   H   OCH.sub.3                                                                           OCH.sub.3                                                                           H                                      CH.sub.2 CH.sub.2 OCOC.sub.3 H.sub.7                                                    COOC.sub.2 H.sub.5                                                                     H   H   F     H     H                                      (CH.sub.2).sub.3 OCOC.sub.2 H.sub.5                                                     COOC.sub.2 H.sub.5                                                                     C.sub.2 H.sub.5                                                                   H   Hi    Cl    H                                      CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           COOCH.sub.2 CH.sub.2 OH                                                                H   H   OCH.sub.3                                                                           OCH.sub.3                                                                           H                                      CH.sub.2 CH.sub.2 OCOC.sub.2 H.sub.5                                                    COOC.sub.2 H.sub.5                                                                     H   H   SCH.sub.3                                                                           H     H                                      CH.sub.2 CH.sub.2 OCOC.sub.2 H.sub.5                                                    COOC.sub.2 H.sub.5                                                                     H   H   SOCH.sub.3                                                                          H     H                                      (CH.sub.2).sub.4 O COC.sub.4 H.sub.9                                                    COOC.sub.2 H.sub.5                                                                     C.sub.6 H.sub.5                                                                   H   H     H     H                                      CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           COO-n-C.sub.4 H.sub.9                                                                  H   H   OCH.sub.3                                                                           OCH.sub.3                                                                           H                                      CH.sub.2 CH.sub.2 OCOC.sub.2 H.sub.5                                                    COOC.sub.2 H.sub.5                                                                     H   H   OCH.sub.3                                                                           H     OCH.sub.3                              (CH.sub.2).sub.3 OCOCH.sub.3                                                            COOC.sub.2 H.sub.5                                                                     H   H   OC.sub.2 H.sub.5                                                                    O-n-C.sub.4 H.sub.9                                                                 H                                      CH.sub.2 CH.sub.2 OCOC.sub.3 H.sub.7                                                    COOC.sub.2 H.sub.5                                                                     H   H   OCH.sub.2 CH.sub.2 O                                                                      H                                      (CH.sub.2).sub.4 OCOCH.sub.3                                                            COOC.sub.2 H.sub.5                                                                     H   H   H     F     H                                      CH.sub.2 CH.sub.2 OCOC.sub.2 H.sub.5                                                    COOC.sub.2 H.sub.5                                                                     H   Cl  H     H     H                                      CH.sub.2 CH.sub.2 OCOC.sub.4 H.sub.9                                                    COO-n-C.sub.4 H.sub.9                                                                  H   H   H     H     H                                      CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           COOC.sub.2 H.sub.5                                                                     H   H   OCH.sub.3                                                                           OCH.sub.3                                                                           OCH.sub.3                              (CH.sub.2).sub.3 OCOC.sub.2 H.sub.5                                                     COOC.sub.2 H.sub.5                                                                     H   Br  H     H     H                                      CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           COOCH.sub.3                                                                            H   CH.sub.3                                                                          H     CH.sub.3                                                                            H                                      CH.sub.2 CH.sub.2 OCOC.sub.3 H.sub.7                                                    COOC.sub.2 H.sub.5                                                                     H   H   t-C.sub.4 H.sub.9                                                                   H     H                                      (CH.sub.2).sub.4 OCOCH.sub.3                                                            COOC.sub.2 H.sub.5                                                                     H   H   n-C.sub.3 H.sub.7                                                                   n-C.sub.3 H.sub.7                                                                   H                                      CH.sub.2 CH.sub.2 OCOC.sub.2 H.sub.5                                                    CH.sub.3 H   H   OCH.sub.3                                                                           OCH.sub.3                                                                           H                                      CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           CH.sub.3 CH.sub.3                                                                          H   OCH.sub.3                                                                           OC.sub.2 H.sub.5                                                                    H                                      (CH.sub.2).sub.3 OCOCH.sub.3                                                            CH.sub.3 n-C.sub.4 H.sub.9                                                                 H   H     H     H                                      CH.sub.2 CH.sub.2 OCOC.sub.2 H.sub.5                                                    CH.sub.3 H   H   SCH.sub.3                                                                           SCH.sub.3                                                                           H                                      CH.sub.2 CH.sub.2 OCOC.sub.2 H.sub.5                                                    CH.sub.3 H   H   SOCH.sub.3                                                                          SOCH.sub.3                                                                          H                                      CH.sub.2 CH.sub.2 OCOC.sub.2 H.sub.5                                                    CH.sub.3 C.sub.2 H.sub.5                                                                   Cl  H     H     H                                      CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           CH.sub.3 C.sub.6 H.sub.5                                                                   H   OCH.sub.3                                                                           OCH.sub.3                                                                           H                                      (CH.sub.2).sub.4 OCOCH.sub.3                                                            CH.sub.3 C.sub.6 H.sub.5                                                                   H   SCH.sub.3                                                                           H     H                                      (CH.sub.2).sub.3 OCOC.sub.2 H.sub.5                                                     C.sub.2 H.sub.5                                                                        H   H   H     H     H                                      (CH.sub.2).sub.3 OCOC.sub.4 H.sub.9                                                     C.sub.2 H.sub.5                                                                        H   H   OCH.sub.3                                                                           OCH.sub.3                                                                           H                                      CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           C.sub.2 H.sub.5                                                                        H   H   Cl    H     H                                      CH.sub.2 CH.sub.2 OCOC.sub.2 H.sub.5                                                    C.sub.2 H.sub.5                                                                        H   H   OC.sub.2 H.sub.5                                                                    OC.sub.7 H.sub.7                                                                    H                                      (CH.sub.2).sub.3 OCOC.sub.2 H.sub.5                                                     C.sub.2 H.sub.5                                                                        H   H   OC.sub.2 H.sub.5                                                                    o-n-C.sub.4 H.sub.9                                                                 H                                      (CH.sub.2).sub.3 OCOC.sub.2 H.sub. 5                                                    C.sub.2 H.sub.5                                                                        H   OCH.sub.3                                                                         OCH.sub.2O  H                                      CH.sub.2 CH.sub.2 OCOC.sub.2 H.sub.5                                                    C.sub.2 H.sub.5                                                                        C.sub.2 H.sub.5                                                                   H   SCH.sub.3                                                                           SCH.sub.3                                                                           H                                      CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           C.sub.2 H.sub.5                                                                        n-C.sub.4 H.sub.9                                                                 H   H     i-C.sub.3 H.sub.7                                                                   H                                      CH.sub.2 CH.sub.2 OCOC.sub.2 H.sub.5                                                    C.sub.2 H.sub.5                                                                        CH.sub.3                                                                          H   O-n-C.sub.4 H.sub.9                                                                 O-n-C.sub.4 H.sub.9                                                                 H                                      CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           C.sub.2 H.sub.5                                                                        C.sub.6 H.sub.5                                                                   H   SOCH.sub.3                                                                          SOCH.sub.3                                                                          H                                      (CH.sub.2).sub.3 OCOCH.sub.3                                                            COCH.sub.3                                                                             H   H   OCH.sub.3                                                                           OCH.sub.3                                                                           H                                      (CH.sub.2).sub.3 OCOCH.sub.3                                                            COCH.sub.3                                                                             H   H   OCH.sub.2 CH.sub.2 O                                                                      H                                      CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           COCH.sub.3                                                                             H   H   CH.sub.3                                                                            CH.sub.3                                                                            H                                      CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           COCH.sub.3                                                                             CH.sub.3                                                                          H   H     Cl    H                                      CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           COCH.sub.3                                                                             C.sub.2 H.sub. 5                                                                  Br  H     H     H                                      CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           COCH.sub.3                                                                             n-C.sub.4 H.sub.9                                                                 H   H     i-C.sub.3 H.sub.7                                                                   H                                      CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           COCH.sub.3                                                                             C.sub.6 H.sub.5                                                                   H   SOCH.sub.3                                                                          SOCH.sub.3                                                                          H                                      CH.sub.2 CH.sub.2 OCOC.sub.6 H.sub.5                                                    COOC.sub.2 H.sub.5                                                                     H   H   OCH.sub.3                                                                           OCH.sub.3                                                                           H                                      (CH.sub.2).sub.4 OCOC.sub.6 H.sub.5                                                     COOC.sub.2 H.sub.5                                                                     H   H   OCH.sub.2O  H                                      CH.sub.2 CH.sub.2 OCOC.sub.6 H.sub.5                                                    H        H   H   OC.sub.2 H.sub.5                                                                    OC.sub.7 H.sub.7                                                                    H                                      (CH.sub.2).sub.3 OCOC.sub.6 H.sub.5                                                     COOC.sub.2 H.sub.5                                                                     CH.sub.3                                                                          H   SCH.sub.3                                                                           H     H                                      CH.sub.2 CH.sub.2 OCOC.sub.6 H.sub.5                                                    CH.sub.3 C.sub.6 H.sub.5                                                                   CH.sub.3                                                                          CH.sub.3                                                                            CH.sub.3                                                                            OCH.sub.3                              (CH.sub.2).sub.4 OCOC.sub.6 H.sub.5                                                     CH.sub.3 CH.sub.3                                                                          H   SOCH.sub.3                                                                          H     H                                      CH.sub.2 CH.sub.2 OCOC.sub.6 H.sub.5                                                    C.sub.2 H.sub.5                                                                        H   H   OC.sub.2 H.sub.5                                                                    O-(n-C.sub.4 H.sub.9)                                                               H                                      CH.sub.2 CH.sub. 2 OCOC.sub.6 H.sub.5                                                   COOC.sub.2 H.sub.5                                                                     H   H   OC.sub.7 H.sub.7                                                                    OCH.sub.3                                                                           H                                      CH.sub.2 CH.sub.2 OCOC.sub.6 H.sub.5                                                    COO-n-C.sub.4 H.sub.9                                                                  H   H   OC.sub.7 H.sub.7                                                                    OCH.sub.3                                                                           H                                      CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           COOC.sub.2 H.sub.5                                                                     H   H   OCH.sub.3                                                                           OC.sub.7 H.sub.7                                                                    H                                      (CH.sub.2).sub.4 OCOC.sub.3 H.sub.7                                                     COOC.sub.2 H.sub.5                                                                     H   H   OC.sub.7 H.sub.7                                                                    H     H                                      (CH.sub.2).sub.3 OCOC.sub.2 H.sub.5                                                     COOC.sub.2 H.sub.5                                                                     H   OC.sub.7 H.sub.7                                                                  OCH.sub.3                                                                           H     H                                      CH.sub.2 CH.sub.2 OCOC.sub.2 H.sub.5                                                    COOC.sub.2 H.sub.5                                                                     H   H   F     OC.sub.7 H.sub.7                                                                    H                                      CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           CH.sub.3 H   H   OC.sub.7 H.sub.7                                                                    OCH.sub.3                                                                           H                                      (CH.sub.2).sub.3 OCOC.sub.6 H.sub.5                                                     CH.sub.3 C.sub.6 H.sub.5                                                                   H   OCH.sub.3                                                                           OCH.sub.3                                                                           H                                      CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           CH.sub.3 n-C.sub.4 H.sub.9                                                                 C.sub.2 H.sub.5                                                                   OC.sub.7 H.sub.7                                                                    H     H                                      CH.sub.2 CH.sub.2 OCOC.sub.3 H.sub.7                                                    C.sub.2 H.sub.5                                                                        H   H   OC.sub.7 H.sub.7                                                                    OC.sub.7 H.sub.7                                                                    H                                      CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           C.sub.2 H.sub.5                                                                        CH.sub.3                                                                          H   OCH.sub.3                                                                           OC.sub.7 H.sub.7                                                                    Br                                     CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           COCH.sub.3                                                                             H   H   OC.sub.7 H.sub.7                                                                    OCH.sub.3                                                                           H                                      CH.sub.2 CH.sub.2 OCOC.sub.6 H.sub.5                                                    COOCH.sub.2 CH.sub.2 OH                                                                H   H   OC.sub.7 H.sub.7                                                                    OCH.sub.3                                                                           H                                      CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           COOC.sub.2 H.sub.5                                                                     H   H   SC.sub.7 H.sub.7                                                                    H     H                                      (CH.sub.2).sub.4 OCOC.sub.2 H.sub.5                                                     COOC.sub.2 H.sub.5                                                                     H   H   SC.sub.7 H.sub.7                                                                    C.sub.2 H.sub.5                                                                     H                                      CH.sub.2 CH.sub.2 OCOC.sub.6 H.sub.5                                                    COOC.sub.2 H.sub.5                                                                     H   H   H     SC.sub.7 H.sub.7                                                                    H                                      CH.sub.2 CH.sub.2 OCOC.sub.3 H.sub.7                                                    COOC.sub.2 H.sub.5                                                                     H   H   SOC.sub.7 H.sub.7                                                                   H     H                                      CH.sub.2 CH.sub.2 OCOC.sub.6 H.sub.5                                                    COOC.sub.2 H.sub.5                                                                     H   H   H     SOC.sub.7 H.sub. 7                                                                  H                                      CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           COO-n-C.sub.4 H.sub.9                                                                  H   H   CH.sub.3 COO                                                                        OCH.sub.3                                                                           H                                      (CH.sub.2).sub.4 OCOC.sub.2 H.sub.5                                                     COOC.sub.2 H.sub.5                                                                     H   H   C.sub.3 H.sub.7 COO                                                                 OCH.sub. 3                                                                          H                                      CH.sub.2 CH.sub.2 OCOC.sub.6 H.sub.5                                                    COOCH.sub.3                                                                            H   HCOO                                                                              OCH.sub.3                                                                           H     H                                      (CH.sub.2).sub.3 OCOCH.sub.3                                                            COOC.sub.2 H.sub.5                                                                     H   H   H     C.sub.2 H.sub.5 COS                                                                 H                                      CH.sub.2 CH.sub.2 OCOC.sub.3 H.sub.7                                                    COOC.sub.2 H.sub.5                                                                     H   H   C.sub.6 H.sub.5 COO                                                                 OCH.sub.3                                                                           H                                      CH.sub.2 CH.sub.2 OCOCH.sub.3                                                           COOC.sub.2 H.sub.5                                                                     H   H   CH.sub.3 COO                                                                        H     H                                      (CH.sub.2).sub.4 OCOC.sub.2 H.sub.5                                                     COOC.sub.2 H.sub.5                                                                     H   H   C.sub.6 H.sub.5 COO                                                                 H     H                                      __________________________________________________________________________

example xxxiv ethyl Benzo[g]Quinazolin-4(3H)-One-2-Carboxylate

A. benzo-isatoic Anhydride

Anthranilic acid (25.0 g., 0.133 mole) is dissolved, warming ifnecessary, in a mixture of water (50 ml.), concentrated hydrochloricacid (50 ml.) and dioxane (100 ml.). Phosgene is passed into thesolution with good stirring at such a rate that bubbles of the gasescape slowly into an ammonia scrubber attached to the reaction flask.The temperature is held below 50° C. by regulating the rate ofintroduction of the phosgene. After passing phosgene into the mixturefor four hours, the residual phosgene is blown out by passing airthrough the mixture. The mixture is cooled and the product filtered off,washed with cold water and dried to give 26.46 g. (93.5%) of theanhydride. M.P. 390° C. (dec.).

B. 2-aminonaphthalene-3-Carboxamide

Ammonia is intermittently bubbled into a suspension of benzoisatoianhydride (5.0 g., 2.25 millimoles) and ethanol (80 ml.) for a period oftwo days. The bright green solid which formed is filtered from thereaction mixture, dried and then recrystallized from ethanol. Yield =1.95 g. (46%) of the title amide. M.P. 234°-235° C. (m/e - 186).

C. ethyl benzo[g]quinazolin-4(3H)-one-2-carboxylate

Diethyl oxalate (2.35 g., 16.1 millimoles), sodium methoxide (10 m and2-aminonaphthalene-3-carboxamide (1.50 g., 8.05 millimoles) are mixedtogether and heated at reflux for two days. The mixture is then cooledin an ice bath and the brown precipitate recovered by filtration. It isrecrystallized from ethanol to give 1.76 g. (79% yield) of the desiredester. M.P. 240°-242° C.

Analysis: Calcd. for C₁₅ H₁₂ N₂ O₃ : C, 67.15; H, 4.51; N, 10.44%.Found: C, 65.44; H, 4.50; N, 10.17%.

d. the ester is hydrolyzed to the disodium salt as follows:

The ester (1.05 g., 3.92 millimoles) is added to 15% aqueous sodiumhydroxide (20 ml.) and the mixture stirred for two days. It is thenacidified at room temperature with 10% hydrochloric acid to pH 2. andevaporated to dryness under reduced pressure. The residue is treatedwith methanol-water (1:1, 50 ml.) and the suspension filtered to give0.70 g. of yellow crystals. The crystals are added to a saturatedsolution of aqueous sodium bicarbonate (35 ml.) and water (20 ml.). Themixture is stirred for a half-hour and the yellow solid filtered off anddried. Yield = 0.641 g. (54.7%). M.P. 340° C. (dec.).

Analysis: Calcd. for C₁₃ H₆ N₂ O₃.2Na.H₂ O: C, 51.31; H, 3.28; N, 9.06;Na, 14.10% Found: C, 51.34; H, 3.05; N, 9.24; Na, 11.14%.

E. repetition of this hydrolysis procedure but using potassiumbicarbonate or ammonium bicarbonate in place of sodium bicarbonateaffords the dipotassium salt and the diammonium salt.

EXAMPLE XXXV Alkyl Benzo[g]Quinazolin-4(3H)-One-2-Carboxylates

The following alkyl benzo[g]quniazolin-4(3H)-one-2-carboxylates areprepared from the appropriate reactants by the procedure of ExampleXXXIV.

    ______________________________________                                         ##STR17##                                                                    R° R.sub.2    R.sub.3     R.sub.4                                      ______________________________________                                        OC.sub.2 H.sub.5                                                                        H          H           OC.sub.2 H.sub.5                             OCH.sub.3 H          OCH.sub.3   OCH.sub.3                                    O-n-C.sub.4 H.sub.9                                                                     H          OCH.sub.3   OCH.sub.3                                    OC.sub.2 H.sub.5                                                                        H          OCH.sub.2O                                               OC.sub.2 H.sub.5                                                                        H          H           O-n-C.sub.4 H.sub.9                          OC.sub.2 H.sub.5                                                                        H          O-n-C.sub.3 H.sub.7                                                                       O-n-C.sub.3 H.sub.7                          OCH.sub.3 H          CH.sub.3    H                                            O-i-C.sub.3 H.sub.7                                                                     H          H           CH.sub.3                                     OC.sub.2 H.sub.5                                                                        CH.sub.3   H           H                                            OC.sub.2 H.sub.5                                                                        CH.sub.3   CH.sub.3    H                                            OC.sub.2 H.sub.5                                                                        H          CH.sub.3    CH.sub.3                                     O-n-C.sub.3 H.sub.7                                                                     H          H           C.sub.2 H.sub.5                              O-n-C.sub.3 H.sub.7                                                                     H          H           n-C.sub.3 H.sub.7                            O-n-C.sub.4 H.sub.9                                                                     H          H           i-C.sub.3 H.sub.7                            OCH.sub.3 H          n-C.sub.3 H.sub.7                                                                         H                                            OCH.sub.3 H          n-C.sub.3 H.sub.7                                                                         n-C.sub.3 H.sub.7                            OC.sub.2 H.sub.5                                                                        H          t-C.sub.4 H.sub.9                                                                         H                                            OC.sub.2 H.sub.5                                                                        CH.sub.3   H           CH.sub.3                                     OCH.sub.3 H          H           Br                                           OCH.sub.3 H          Br          H                                            OCH.sub.3 Br         H           H                                            OC.sub.2 H.sub.5                                                                        Cl         H           H                                            OC.sub.2 H.sub.5                                                                        H          Cl          H                                            OC.sub.2 H.sub.5                                                                        H          H           Cl                                           O-n-C.sub.4 H.sub.9                                                                     H          I           H                                            O-n-C.sub.4 H.sub.9                                                                     I          H           H                                            OC.sub.2 H.sub.5                                                                        H          F           H                                            OC.sub.2 H.sub.5                                                                        H          H           F                                            OC.sub.2 H.sub.5                                                                        SCH.sub.3  H           H                                            OCH.sub.3 H          SCH.sub.3   H                                            O-n-C.sub.4 H.sub.9                                                                     H          H           SCH.sub.3                                    OCH.sub.3 H          SC.sub.7 H.sub.7                                                                          H                                            O-n-C.sub.3 H.sub.7                                                                     SC.sub.7 H.sub.7                                                                         H           H                                            OC.sub.2 H.sub.5                                                                        H          H           SC.sub.7 H.sub.7                             OCH.sub.3 H          OC.sub.2 H.sub.5                                                                          H                                            OC.sub.2 H.sub.5                                                                        H          O-n-C.sub.4 H.sub.9                                                                       H                                            OC.sub.2 H.sub.5                                                                        H          OC.sub.7 H.sub.7                                                                          H                                            OC.sub.2 H.sub.5                                                                        OC.sub.7 H.sub.7                                                                         H           H                                            ______________________________________                                    

the methyl and ethyl esters in the above tabulation are converted to thecorresponding n-butyl esters by the transesterification procedure ofExample VIII, and to the acids, the disodium, diammonium and dipotassiumsalts according to the hydrolysis procedure of Example XXXIV-D.

The thioethers are converted to the corresponding sulfinyl derivativesby oxidation with hydrogen peroxide accoding to the procedure of ExampleXXII.

Benzyl ethers and benzylthio ethers are debenzylated by reaction withtrifluoroacetic acid as described in Example XV to the correspondinghydroxy and thiol compounds.

EXAMPLE XXXVI

The hydroxy compounds of Example XXXV are converted to correspondingacyl derivatives by the procedure of Example XIX. The following are thusprepared;

    ______________________________________                                         ##STR18##                                                                     R°   R.sub.2     R.sub.3     R.sub.4                                  ______________________________________                                        OCH.sub.3    H           CH.sub.3 COO                                                                              H                                        O-n-C.sub. 3 H.sub.7                                                                       CH.sub.3 COO                                                                              H           H                                        OCH.sub.3    H           C.sub.6 H.sub.5 COO                                                                       H                                        OC.sub.2 H.sub.5                                                                           H           C.sub.6 H.sub.5 COO                                                                       H                                        OC.sub.2 H.sub.5                                                                           HCOO        H           H                                        O-n-C.sub. 4 H.sub.9                                                                       CH.sub.3 COO                                                                              H           H                                        OCH.sub.3    C.sub.3 H.sub.7 COO                                                                       H           H                                        ______________________________________                                    

example xxxvii benzo[g]Quinazolin-4(3H)-One-2-Carboxamides

Following the procedure of Example IX but using the appripriate2-aminonaphthalene-3-carboxamide in place of2-aminoquinolin-3-carboxamide, the amides corresponding to the esterproduces of Examples XXXIV and XXXV are prepared. The compounds have theformula: ##STR19##

EXAMPLE XXXVIII Benzo[g]Quniazolin-4(3H)-One-2-Hydroxamic Acids

The esters products of Example XXXIV-XXXVI are converted to thecoresponding hydroxamic acids by the procedure of Example XIV. Thecompounds have the formula: ##STR20##

EXAMPLE XXXIX Ethyl Pyrido[2,3-d]Pyrimidin-4(3H)-One-2-Carboxylate

A mixture of diethyl oxalate (530 mg., 3.65 millimoles) and2-aminonicotinamide (500 mg., 3.65 millimoles) is heated to refluxovernight. The mixture is then cooled in an ice bath and the yellowsolid which precipitated filtered off and recrystallized fromenzene/hexane (1:1). Yield = 196 mg. (30%). M.P. 190°-192° C.

Analysis: Calcd. for C₁₀ H₉ N₃ O₃ : C, 54.79, H, 4.13; N, 19.17%. Found:C, 54.88; H, 4.11; N, 19.33%.

Hydrolysis of the ester according to the procedure of Example XXXIV-Daffords the acid and the disodium salt.

EXAMPLE XL

Repetition of the procedure of Example XXV but using the appropriate2-aminonicotinamide in place of6,7-dimethoxy-2-aminoquinoline-3-carboxamide produces the followingcompounds:

    ______________________________________                                         ##STR21##                                                                    R.sub.2       R.sub.3        R.sub.4                                          ______________________________________                                        H             H              H                                                CH.sub.3      H              CH.sub.3                                         H             OCH.sub.3      CH.sub.3                                         H             OCH.sub.3      H                                                H             t-C.sub.4 H.sub.9                                                                            H                                                Cl            H              H                                                CH.sub.3      Br             CH.sub.3                                         H             SCH.sub.3      H                                                CH.sub.3      SCH.sub.3      H                                                H             SOCH.sub.3 *   H                                                CH.sub.3      SOCH.sub.3 *   H                                                CH.sub.3      SC.sub.7 H.sub.7                                                                             H                                                CH.sub.3      SC.sub.7 H.sub.7                                                                             CH.sub.3                                         CH.sub.3      SOC.sub.7 H.sub.7 *                                                                          H                                                CH.sub.3      SOC.sub.7 H.sub.7 *                                                                          CH.sub.3                                         CH.sub.3      C.sub.2 H.sub.5                                                                              CH.sub.3                                         CH.sub.3      n-C.sub.3 H.sub.7                                                                            CH.sub.3                                         CH.sub.3      n-C.sub.4 H.sub.9                                                                            H                                                CH.sub.3      Cl             CH.sub.3                                         H             Cl             H                                                CH.sub.3      C.sub.2 H.sub.5                                                                              H                                                H             Cl             CH.sub.3                                         CH.sub.3      OC.sub.2 H.sub.5                                                                             H                                                CH.sub.3      O-n-C.sub.4 H.sub.9                                                                          CH.sub.3                                         CH.sub.3      OC.sub.7 H.sub.7                                                                             H                                                OC.sub.7 H.sub.7                                                                            H              H                                                ______________________________________                                         *Produced by oxidation of the corresponding thioethers according to the       procedure of Example XXII.                                               

The benzyl ethers and benzylthio ethers listed above are debenzylated bytreatment with trifluoroacetic acid to afford the corresponding hydroxyand thiol compounds according to the procedure of Example XV.

EXAMPLE XLI 2-Ethylpyrido[2,3-d]Pyrimidin-4(3H)-Ones

Concentrated sulfuric acid (0.5 ml.) is added to a mixture of2-aminonicotinamide (0.24 g., 0.002 mole) in propionic anhydride (10ml.) at 60° C. and the resulting mixture stirred for one hour. It isthen cooled to room temperature and poured into water (25 ml.). Theaqueous mixture is stirred, made basic with 6N sodium hydroxide andstirred overnight. Upon acidification to pH 5.0 with 10% hydrochloricacid the desired product precipitates. It is filtered off and dried.

The following compounds are prepared in like manner from appropriatereactants:

    ______________________________________                                         ##STR22##                                                                    R.sub.2         R.sub.3   R.sub.4                                             ______________________________________                                        H             OCH.sub.3   CH.sub.3                                            H             OCH.sub.3   H                                                   H             Cl          H                                                   H             SCH.sub.3   H                                                   H             t-C.sub.4 H.sub.9                                                                         H                                                   CH.sub.3      Br          CH.sub.3                                            CH.sub.3      SCH.sub.3   H                                                   CH.sub.3      Cl          H                                                   CH.sub.3      SOCH.sub.3 *                                                                              H                                                   H             SOCH.sub.3 *                                                                              H                                                   H             C.sub.2 H.sub.5                                                                           H                                                   H             CH.sub.3    H                                                   CH.sub.3      Cl          CH.sub.3                                            CH.sub.3      SC.sub.7 H.sub.7                                                                          H                                                   CH.sub.3      SC.sub.7 H.sub.7                                                                          CH.sub.3                                            CH.sub.3      SOC.sub.7 H.sub.7 *                                                                       H                                                   H             Cl          CH.sub.3                                            ______________________________________                                         *Prepared by oxidation of the corresponding thio compound according to th     procedure of Example XXII.                                               

Debenzylation of the benzyl ethers and benzylthio ethers by treatmentwith trifluoroacetic acid according to the procedure of Example XVaffords the corresponding hydroxy and thiol compounds.

EXAMPLE XLII 2-Acetylpyrimido[2,3-d]Pyrimidin-4(3H)-Ones

The products of Example XLI are oxidized by selenium dioxidesubstantially accordding to the procedure of Example XXVII to providecompounds of the formula: ##STR23##

EXAMPLE XLIII

Repetition of the procedure of Example XXXV reactants produces thefollowing compounds:

    ______________________________________                                         ##STR24##                                                                    R°    R.sub.2   R.sub.3     R.sub.4                                    ______________________________________                                        OC.sub.2 H.sub.5                                                                           H         CH.sub.3    H                                          O-n-C.sub. 3 H.sub.7                                                                       CH.sub.3  H           CH.sub.3                                   OCH.sub.3    H         CH.sub.3    CH.sub.3                                   OC.sub.2 H.sub.5                                                                           CH.sub.3  H           CH.sub.3                                   OC.sub.2 H.sub.5                                                                           CH.sub.3  CH.sub.3    CH.sub.3                                   OCH.sub.3    CH.sub.3  Br          CH.sub.3                                   OC.sub.2 H.sub.5                                                                           Cl        H           H                                          O-n-C.sub. 4 H.sub.9                                                                       H         H           H                                          OCH.sub.3    H         H           CH.sub.3                                   OC.sub.2 H.sub.5                                                                           H         H           i-C.sub.3 H.sub.7                          OCH.sub.3    H         H           i-C.sub.4 H.sub.9                          OC.sub.2 H.sub.5                                                                           H         OCH.sub.3   CH.sub.3                                   O-n-C.sub. 4 H.sub.9                                                                       H         OCH.sub.3   H                                          OC.sub.2 H.sub.5                                                                           CH.sub.3  H           H                                          OC.sub.2 H.sub.5                                                                           H         n-C.sub.3 H.sub.7                                                                         H                                          OCH.sub.3    H         t-C.sub.4 H.sub.9                                                                         H                                          OC.sub.2 H.sub. 5                                                                          H         Cl          H                                          O-i-C.sub.3 H.sub.7                                                                        H         Br          H                                          OC.sub.2 H.sub.5                                                                           CH.sub.3  Cl          H                                          OC.sub.2 H.sub.5                                                                           H         Cl          CH.sub.3                                   OCH.sub.3    CH.sub.3  Cl          CH.sub.3                                   OC.sub.2 H.sub.5                                                                           H         SCH.sub.3   H                                          OC.sub.2 H.sub.5                                                                           CH.sub.3  SCH.sub.3   CH.sub.3                                   OC.sub.2 H.sub.5                                                                           CH.sub.3  SC.sub.7 H.sub.7                                                                          H                                          OCH.sub.3    CH.sub.3  SC.sub.7 H.sub.7                                                                          CH.sub.3                                   OCH.sub.3    CH.sub.3  OC.sub.7 H.sub.7                                                                          H                                          OC.sub.2 H.sub.5                                                                           OC.sub.7 H.sub.7                                                                        H           H                                          OC.sub.2 H.sub.5                                                                           CH.sub.3  O-n-C.sub. 4 H.sub.9                                                                      CH.sub.3                                   OC.sub.2 H.sub.5                                                                           H         SOCH.sub.3 *                                                                              H                                          OC.sub.2 H.sub.5                                                                           CH.sub.3  SOCH.sub.3 *                                                                              CH.sub.3                                   OC.sub.2 H.sub.5                                                                           CH.sub.3  SOC.sub.7 H.sub.7 *                                                                       H                                          OCH.sub.3    CH.sub.3  SOC.sub.7 H.sub.7 *                                                                       CH.sub.3                                   ______________________________________                                         *Prepared by oxidation according to the procedure of Example XXII.       

Hydrolysis of the ester by the method of Example XXIII-D produces theacid, and disodium salt derivatives. Debenzylation of benzyl ethers andbenxylthio ethers in the manner of Example XV affords the correspondinghydroxy and thiol compounds.

EXAMPLE XLIV

The hydroxy and thiol compounds of Examples XL-XLIII are converted toacyloxy derivatives by the procedure of Example XIX. In this manner theformyloxy, acetoxy, butyryloxy and benzyloxy derivatives are prepared.

EXAMPLE XLV Pyrido[2,3-d]Pyrimidin-4(3H)-One-2-Carboxamides

The procedure of Example IX is repeated but using the appropriate2-aminonicotinamide as reactant in place of2-aminonaphthalene-3-carboxamide to produce the amides corresponding tothe esters of Examples XXXIX and XLIII.

EXAMPLE XLVI Pyrido[2,3-d]Pyrimidin-4(3H)-One-2-Hydroxamic Acids

The esters of Examples XXXIX and XLIII are converted by the procedure ofExample XIV to hydroxamic acids of the formula: ##STR25##

EXAMPLE XLVII

The ester products of Examples I, III-VI, VIII, X, XII, XIII, XVIII,XXVIII, XXXIV-XXXVI, XXXIX, and XLIII are converted to the correspondingacids of the procedure of Example II-D, and to the disodium, dipotassiumand diammonium salts by the procedure of Examples XXXIV-D and XXXIV-E.

The acids are converted to the calcium, magnesium, aluminum,triethylamine, tri-n-butylamine, piperidine, triethanolamine,diethylamino-ethylamine, N,N'-dibenzylethylenediamine and pyrrolidine byreaction with an equivalent amount of the appropriate base (Ca(OH)₂,Mg(OH)₂, A1(OH)₃) or amine in water or ethanol followed by filtration ofthe salt if insoluble or by evaporation of the solvent if the salt issoluble therein.

EXAMPLE XLVIII Injectable Preparation

One thousand grams of ethylpyrimido[4,5-b]quniolin-4(3H)-one-2-carboxylate are intimately mixed andground with 2500 grams of sodium ascorbate. The ground, dry mixture isplaced in vials and sterilized with ethylene oxide after which the vialsare sterilely stoppered. For intravenous administration, sufficientwater is added to the materials in the vials to form a solutioncontaining 5.0 mg. of active ingredient per milliliter of injectablesolution.

EXAMPLE XLIX Tablets

A tablet base is prepared by blending the following ingredients in theproportion by weight indicated:

    ______________________________________                                        Sucrose, U.S.P.        80.3                                                   Tapioca Starch         13.2                                                   Magnesium Stearate      6.5                                                   ______________________________________                                    

Into this tablet base there is blended sufficient ethyl 7,8-dimethoxypyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate to provide tabletscontaining 20, 100 and 250 mg. of active ingredient per tablet. Thecompositions are each compressed into tablets, each weighing 360 mg., byconventional means.

EXAMPLE L Capsules

A blend is prepared containing the following ingredients:

    ______________________________________                                        Calcium carbonate, U.S.P.                                                                            17.6                                                   Dicalcium phosphate    18.8                                                   Magnesium trisilicate, U.S.P.                                                                        5.2                                                    Lactose, U.S.P.        5.2                                                    Potato starch          5.2                                                    Magnesium stearate A   0.8                                                    Magnesium stearate B    0.35                                                  ______________________________________                                    

To this blend is added sufficient ethyl7,8-dimethoxypyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate to providecapsules containing10, 25 and 50 mg. of active ingredient per capsule.The compositions are filled into conventional hard gelatin capsules inthe amount of 350 mg. per capsule.

In like manner, capsules containing 2.0 mg. and 6.0 mg. of drug,ethyl7,8-dimethoxypyrimido[4,5-b]quinoline-4(3H)-one-2-carboxylate, andhaving 300 mg. of the following blends per capsule are prepared

    ______________________________________                                        Ingredients        Weight mg/capsule                                          ______________________________________                                        Drug               2.00                                                       N-methylglucamine  18.00                                                      Lactose, Anhydrous 241.20                                                     Corn Starch, Anhydrous                                                                           30.00                                                      *Talc              8.80                                                                          300.00                                                     Drug               6.00                                                       N-methylglucamine  18.00                                                      Lactose, Anhydrous 237.20                                                     Corn Starch, Anhydrous                                                                           30.00                                                      *Talc              8.80                                                                          300.00                                                     ______________________________________                                         *Talc added before encapsulation                                         

EXAMPLE LI Suspension

A suspension of pyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylic acid isprepared with the following composition:

    ______________________________________                                        Effective ingredient  25.00 g.                                                70% aqueous sorbitol 741.29 g.                                                Glycerine, U.S.P.    185.35 g.                                                Gum acacia (10% solution)                                                                          100.00 ml.                                               Polyvinylpyrrolidone  0.50 g.                                                 Distilled water      sufficient to make                                                            1 liter                                                  ______________________________________                                    

To this suspension, various sweeteners and flavorants are added toimprove the palatability of the suspension. The suspension containsapproximately 25 mg. of effective agent per milliliter.

EXAMPLE LII

In like manner, the remaining products of this invention are formulatedinto tablets, capsules, solutions and suspensions.

EXAMPLE LIII Solution

A solution of ethyl2-methylpyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate is prepared withthe following composition:

    ______________________________________                                        Effective ingredient                                                                              6.04      grams                                           Magnesium chloride hexahydrate                                                                    12.36     grams                                           Monoethanolamine    8.85      ml.                                             Propylene glycol    376.00    grams                                           Water, distilled    94.00     ml.                                             ______________________________________                                    

The resultant solution has a concentration of effective ingredient of 10mg./ml. and is suitable for parenteral and, especially, forintramuscular administration.

EXAMPLE LIV Aerosol Suspension

A mixture of ethyl7,8-dimethoxypyrimidin[4,5-b]quinolin-4(3H)-one-2-carboxylate(antiallergy agent) and the other ingredients under (a) in the examplesbelow are micronized to a particle size of 1 to 5 microns in a ballmill. The resulting slurry is then placed in a container equipped with avalve and propellant (b) introduced by pressure filling through thevalve nozzle to a gauge pressure of approximately 35-40 pounds persquare inch at 20° C.

    ______________________________________                                        Suspension A              Percent                                             ______________________________________                                        (a)    Antiallergy agent      0.25                                                   Isopropyl myristate    0.10                                                   Ethanol                26.40                                           (b)    60-40% mixture of      73.25                                                  1,2-dichlorotetrafluoroethane-                                                1-chloropentafluoroethane                                              Suspension B                                                                  (a)    Antiallergy agent      0.25                                                   Ethanol                26.50                                           (b)    A 60-40% mixture of    73.25                                                  1,2-dichlorotetrafluoroethane-                                                1-chloropentafluoroethane.                                             ______________________________________                                    

EXAMPLE LV Aerosol Administration

An aqueous solution of ethyl7,8-dimethoxypyrimido[4,5-b]quinolin-4(3H)-one2-carboxylic acid (Drug A,containing 3 mg. of drug per ml. of solution) is placed in a standardnebulizer such as is available from the Vaponephrine Co., Edison, N.J.The solution is sprayed under an air pressure of 6 lbs. per square inchinto a closed 8" × 8" × 12" plastic container for 6 minutes. Thecontainer has four openings to acommodate the heads of four rats. Fourrats are exposed to the drug simultaneously with only their heads comingin contact with the aerosol. Disodium cromoglycate (Drug B, 50 mg./ml.)is used as a basis for comparison. The results obtained in the PCAreaction above are tabulated below:

    ______________________________________                                                        Time Interval between                                                                          % Animals                                    Drug Concn.     Drug and Challenge                                                                             Protected                                    ______________________________________                                        A     3 mg/ml.  0 min.           82                                           A     3 mg./ml. 5 min.           56                                           B    50 mg./ml. 0 min.            0                                           B    50 mg./ml. 5 min.            0                                           ______________________________________                                    

PREPARATION A 2-Amino-5-Alkylnicotinamides

The following 2-amino-5-alkylnicotinamides are produced from thecorresponding 2-amino-5-alkylnicotinonitriles via treatment withalkaline hydrogen peroxide according to the procedure of Taylor et al.,J. Org. Chem. 19, 1633-9 (1954).

    ______________________________________                                         ##STR26##                                                                             R.sub.3                                                              ______________________________________                                                 C.sub.2 H.sub.5                                                               n-C.sub.3 H.sub.7                                                             i-C.sub.3 H.sub.7                                                             n-C.sub.4 H.sub.9                                                             t-C.sub.4 H.sub.9                                                             s-C.sub.4 H.sub.9                                                    ______________________________________                                    

preparation b 2-amino-5-Halonicotinic Acids and Amides

A. 2-amino-5-chloronicotinic acid and hydrochloride

A suspension of 40.0 g. of 2-aminonicotinic acid in 2.1. of acetic acidis stirred while chlorine gas is bubbled through the reaction mixture ata moderate rate for 1.25 hours. The resulting solution is allowed tostir at ambient temperatures for 20 hours, and is then treated with anequal volume of diethyl ether. The resulting precipitate of2-amino-5-chloronicotinic acid hydrochloride is filtered, washed withether and dried in vacuo at 80° C. for several hours, 51.0 g., m.p. 251°C. (dec.).

The free acid is obtained by treating a cold aqueous solution of thehydrochloride salt with sufficient ammonium hydroxide to provide a pH 5.The resulting product is filtered, washed with a small amount of acetoneand dried in vacuo.

B. 2-amino-5-bromonicotinic acid and hydrobromide

2-Aminonicotinic acid (3.6 g.) in 450 ml. of acetic acid is treateddropwise over a period of 10-15 minutes with 4 ml. of bromine in 50 ml.of acetic acid. The reaction mixture is allowed to stir at roomtemperature for 1.5-2 hours, and is then diluted with 2 liters ofdiethyl ether. The precipitate which forms, 2-amino-5-bromonicotinicacid hydrobromide, is filtered and dried, 5.6 g., m.p. 280° C. (dec.).

The free acid is liberated by adding sufficient ammonium hydroxide to anaqueous solution of the hydrobromide salt to provide a solution of pH 5.The resulting free acid is filtered from the cooled mixture and dried invacuo.

C. 2-amino-5-chloro-6-methylnicotinic acid hydrochloride

In a manner similar to that of Preparation B-A,2-amino-6-methylnicotinic acid is chlorinated in acetic acid to providethe desired product.

D. 2-amino-4-methyl-5-chlorotinic acid hydrochloride

3-Cyano-4-methylpyridine, Webb et al., J. Am. Chem. Soc. 66, 1456 (1944)is converted via the sequences of Taylor et al., J. Org. Chem. 19, 1633(1954) to 2-amino-4-methylnicotinic acid, which under the conditions ofPreparation B-A is chlorinated at the 5-position to provide the desiredintermediate, 2-amino-4-methyl-5-chloronicotinic acid hydrochloride.

E. 2-amino-4-methyl-5-bromonicotinic acid hydrobromide

In a manner analogous to that of Preparation B-B,2-amino-4-methylnicotinic acid is brominated in an acetic acid solventto provide the desired compound in good yield.

F. 2-amino-4,6-dimethyl-5-chloronicotinic acid hydrochloride

Chlorine gas is bubbled through a solution of 1.89 g of2-amino4,6-dimethylnicotinic acid hydrochloride in 150 ml. of aceticacid at 36° C. for 20-25 minutes. The resulting solid si filtered,washed with diethyl ether and dried, 1.29 g. m.p. 232° -234° C. (dec.).

G. 2-Amino-5-chloro-6-and 4-methylnicotinamide

Fifty grams of 2-amino-5-chloro-6-methylnicotinic acid hydrochloride isadded in small portions to 185 ml. of cold (3° C.) acetyl chloridecontaining 80 g. of phosphorous pentachloride and the resulting reactionmixture allowed to stir at room temperature for 16 hours. Theprecipitate which forms is filtered, washed with 150 ml. of methylenechloride and partially dissolved in 1.2 liters of acetonitrile. Whilethe solution of 2-amino-5-chloronicotinic acid chloride is being stirredat ambient temperatures, ammonia gas is bubbled through the slurry for40 min. at a moderate rate. The solids are filtered and the residue,remaining after the filtrate is concentrated to dryness, is partiallydissolved in acetone. The acetone suspension is filtered and thefiltrate concentrated in vacuo to give 13.9 g. of the desirednicotinamide, m.p. 227°-229° C.

In like manner the remaining nicotinic acid derivatives described aboveare converted to the corresponding amides.

PREPARATION C 2-Amino-5-Alkylnicotinonitriles

2-Amino-4-methyl-5-ethylnicotinonitrile

To 67.0 (0.5 mole) of 1-methylbutylidene malononitrile (Cope, et al., J.Am. Chem. Soc. 63, 733 (1941) is added 260 ml. of acetic anhydride and50 ml. of triethyl orthoformate and the resulting solution heated toreflux for 18 hours. The reaction mixture is concentrated under reducedpressure, and the residue is dissolved in 300 ml. of acetonitrile.Ammonia gas is bubbled through the reaction mixture at a moderate ratefor 2 hours and the mixture then heated to reflux for 4 hours. Thesolvent is removed from the filtered mixture under reduced pressure andthe residual material triturated with diethyl ether. Filtration anddrying give the desired crude product.

The above reaction procedure is repeated, employing the indicatedmalononitrile and ortho ester starting materials to provide thecorresponding substituted 2-aminonicotinonitriles:

    __________________________________________________________________________     ##STR27##                                                                    Starting Materials        Product                                             Malononitrile     ortho ester                                                                           R.sub.4                                                                           R.sub.3                                                                             R.sub.2                                   __________________________________________________________________________    CH.sub.3 CH.sub.2 CH.sub.2 C(CH.sub.3)C(CN).sub.2                                               CH.sub.3 C(OC.sub.2 H.sub.5).sub.3                                                    CH.sub.3                                                                          C.sub.2 H.sub.5                                                                     CH.sub.3                                  CH.sub.3 (CH.sub.2).sub.3 CHC(CN).sub.2                                                         CH.sub.3 C(OC.sub.2 H.sub.5).sub.3                                                    CH.sub.3                                                                          n-C.sub.3 H.sub.7                                                                   H                                         CH.sub.3 (CH.sub.2).sub.3 C(CH.sub.3)C(CN).sub.2                                                CH.sub.3 C(OC.sub.2 H.sub.5).sub.3                                                    CH.sub.3                                                                          n-C.sub.3 H.sub.7                                                                   CH.sub.3                                  (CH.sub.3).sub.2 CHCH.sub.2 C(CH.sub.3)C(CN).sub.2                                              CH.sub.3 C(OC.sub.2 H.sub.5).sub.3                                                    CH.sub.3                                                                          i-C.sub.3 H.sub.7                                                                   CH.sub.3                                  CH.sub.3 (CH.sub.2).sub.4 CHC(CN).sub.2                                                         CH.sub.3 C(OC.sub.2 H.sub.5).sub.3                                                    CH.sub.3                                                                          n-C.sub.4 H.sub.9                                                                   H                                         CH.sub.3 CH(C.sub.2 H.sub.5)CH.sub.2 C(CH.sub.3)C(CN).sub.2                                     HC(OC.sub.2 H.sub.5).sub.3                                                            H   s-C.sub.4 H.sub.9                                                                   CH.sub.3                                  (CH.sub.3).sub.3 CCH.sub.2 C(CH.sub.3)C(CN).sub.2                                               CH.sub.3 C(OC.sub.2 H.sub.5).sub.3                                                    CH.sub.3                                                                          t-C.sub.4 H.sub.9                                                                   CH.sub.3                                  __________________________________________________________________________

the nitriles are converted to the corresponding amides by the procedureof Taylor et al., J. Org. Chem. 19, 1633-g (1954):

PREPARATION D 2-Amino-4-Substituted-Quinoline-3-Carboxamides

The appropriate substituted 2-aminobenzophenone oralkyl-(2-aminophenyl)ketone of the formula ##STR28## wherein the Rvariables have the values given below, and malononitrile are mixedtogether in pyridine in a 1:2 molar ratio and heated under reflux for 24hours. Sufficient pyridine is used to achieve solution of the reactants.The mixture is then cooled and concentrated in vacuo. The precipitate iscollected, washed with ethanol and recrystallized from ethanol.

The thus-obtained nitrile is hydrolyzed by heating in excess of 95%sulfuric acid for three hours on a steam bath. The mixture is thenpoured into a large volume of ice water and allowed to stand overnight.The aqueous, mixture is filtered if necessary and the filtrate madealkaline (pH. 11-11.5) with 5N sodium hydroxide. The amide productprecipitates and is recovered by filtration. It is washed with water anddried.

The following compounds are thus prepared:

    ______________________________________                                         ##STR29##                                                                    R.sub.2  R.sub.3   R.sub.4   R.sub.5 R.sub.1                                  ______________________________________                                        H        H         H         Cl      C.sub.6 H.sub.5                          H        Cl        H         H       C.sub.6 H.sub.5                          H        Br        H         H       C.sub.6 H.sub.5                          H        F         H         H       C.sub.6 H.sub.5                          H        H         CH.sub.3  H       C.sub.6 H.sub.5                          H        Cl        Cl        H       C.sub.6 H.sub.5                          H        CH.sub.3  CH.sub.3  H       C.sub.6 H.sub.5                          H        OCH.sub.3 H         H       C.sub.6 H.sub.5                          H        H         OCH.sub.3 H       C.sub.6 H.sub.5                          H        CH.sub.3  Cl        H       C.sub.6 H.sub.5                          H        H         CH.sub.3  CH.sub.3                                                                              C.sub.6 H.sub.5                          H        Br        H         H       C.sub.2 H.sub.5                          H        H         Cl        H       C.sub.2 H.sub.5                          H        OCH.sub.3 H         H       C.sub.2 H.sub.5                          H        OCH.sub.3 OCH.sub.3 H       C.sub.2 H.sub.5                          H        H         H         H       CH.sub.3                                 H        H         H         H       C.sub.2 H.sub.5                          H        H         H         H       n-C.sub.3 H.sub.7                        H        H         H         H       n-C.sub.4 H.sub.9                        H        H         Br        H       CH.sub.3                                 H        Cl        H         H       CH.sub.3                                 H        H         H         OCH.sub.3                                                                             CH.sub.3                                 H        OCH.sub.3 OCH.sub.3 H       CH.sub.3                                 H        Cl        CH.sub.3  H       CH.sub.3                                 H        H         OCH.sub.3 OCH.sub.3                                                                             CH.sub.3                                 H        H         OC.sub.2 H.sub.5                                                                        OC.sub.2 H.sub.5                                                                      CH.sub.3                                 H        CH.sub.3  CH.sub.3  H       CH.sub.3                                 H        H         I         H       CH.sub.3                                 H        Cl        H         H       n-C.sub.3 H.sub.7                        H        Cl        H         H       n-C.sub.4 H.sub.9                        CH.sub.3 CH.sub.3  CH.sub.3  OCH.sub.3                                                                             CH.sub.3                                 H        OCH.sub.3 H         H       CH.sub.3                                 ______________________________________                                    

preparation e α-cyano-β-(2-Nitro-MethylthiophenylAcrylamides

The following compounds are prepared by reaction of the appropriateα-Cyano-β-(2-nitro-chlorophenyl)acrylamide with sodium methylmercaptideor sodbenzylmercaptide according to the procedures of Example XXI-A.

    ______________________________________                                         ##STR30##                                                                    R.sub.2     R.sub.3    R.sub.4    R.sub.5                                     ______________________________________                                        CH.sub.3 S  H          H          H                                           H           CH.sub.3 S CH.sub.3 S H                                           CH.sub.3 S  H          H          CH.sub.3 S                                  H           H          CH.sub.3 S H                                           C.sub.6 H.sub.5 S                                                                         H          H          H                                           C.sub.6 H.sub.5 S                                                                         H          H          C.sub.6 H.sub.5 S                           H           C.sub.6 H.sub.5 S                                                                        C.sub.6 H.sub.5 S                                                                        H                                           H           C.sub.6 H.sub.5 S                                                                        H          H                                           ______________________________________                                    

preparation f

reaction of the appropriate chloro substituted2-aminonaphthalene-3-carboxamide or the appropriate chlorosubstituted2-aminonicotinamide with sodium methylmercaptide, sodiumbenzylmercaptide, sodium benzylate or the appropriate sodium alcoholateaccording to the procedure of Example XXI-A afford the followingcompounds:

    ______________________________________                                         ##STR31##                                                                    R.sub.2                                                                              R.sub.3  R.sub.4  R.sub.2                                                                              R.sub.3  R.sub.4                              ______________________________________                                        SCH.sub.3                                                                            H        H        H      OC.sub.2 H.sub.5                                                                       H                                    H      SCH.sub.3                                                                              H        H      O-n-C.sub.4 H.sub.9                                                                    H                                    H      H        SCH.sub.3                                                                              H      OC.sub.7 H.sub.7                                                                       H                                    SC.sub.7 H.sub.7                                                                     H        H        OC.sub.7 H.sub.7                                                                     H        H                                    H      SC.sub.7 H.sub.7                                                                       H                                                             H      H        SC.sub.7 H.sub.7                                              ______________________________________                                         ##STR32##                                                                    R.sub.2                                                                              R.sub.3  R.sub.4  R.sub.2                                                                              R.sub.3  R.sub.4                              ______________________________________                                        H      SCH.sub.3                                                                              H        CH.sub.3                                                                             OC.sub.2 H.sub.5                                                                       H                                    CH.sub.3                                                                             SCH.sub.3                                                                              H        CH.sub.3                                                                             O-n-C.sub.4 H.sub.9                                                                    CH.sub.3                             CH.sub.3                                                                             SCH.sub.3                                                                              CH.sub.3 CH.sub.3                                                                             OC.sub.7 H.sub.7                                                                       H                                    CH.sub.3                                                                             SC.sub.7 H.sub. 7                                                                      H        OC.sub.7 H.sub.7                                                                     H        H                                    CH.sub.3                                                                             SC.sub.7 H.sub.7                                                                       CH.sub.3                                                      ______________________________________                                    

preparation g benzyl Ethers of Hydroxy Substituted Benzaldehydes

A mixture of the appropriate hydroxy substituted benzaldehyde (0.66mole), absolute ethanol (450 ml.), anhydrous potassium carbonate (91.5g)and freshly distilled benzyl chloride (95.6g, 0.76 mole) is refluxed for2-3 days. The reaction mixture is filtered to remove the salts and thefiltrate concentrated under reduced pressure. The oily residue is cooledand the resulting solid is recrystallized from an appropriate solventsuch as ethanol.

In this manner, the following benzyl ethers are prepared:

    ______________________________________                                         ##STR33##                                                                    R.sub.2     R.sub.3    R.sub.4    R.sub.5                                     ______________________________________                                        H           H          OC.sub.7 H.sub.7                                                                         H                                           OC.sub.7 H.sub.7                                                                          OCH.sub.3  H          H                                           H           OC.sub.7 H.sub.7                                                                         OC.sub.7 H.sub.7                                                                         H                                           OC.sub.7 H.sub.7                                                                          H          H          H                                           OC.sub.7 H.sub.7                                                                          Br         H          Br                                          H           OCH.sub.3  OC.sub.7 H.sub.7                                                                         Br                                          H           OCH.sub.3  OC.sub.7 H.sub.7                                                                         OCH.sub.3                                   OC.sub.7 H.sub.7                                                                          OCH.sub.3  OCH.sub.3  H                                           H           Br         H          OC.sub.7 H.sub.7                            H           H          H          OC.sub.7 H.sub.7                            C.sub.2 H.sub.5                                                                           OC.sub.7 H.sub.7                                                                         H          H                                           C.sub.2 H.sub.5                                                                           H          OC.sub.7 H.sub.7                                                                         H                                           H           OC.sub.7 H.sub.7                                                                         OC.sub.2 H.sub.5                                                                         H                                           H           OC.sub.2 H.sub.5                                                                         OC.sub.7 H.sub.7                                                                         H                                           H           F          OC.sub.2 H.sub.7                                                                         H                                           H           Br         OC.sub.7 H.sub.7                                                                         H                                           H           Cl         OC.sub.7 H.sub.7                                                                         H                                           H           OC.sub.7 H.sub.7                                                                         H          OCH.sub.3                                   CH.sub.3    CH.sub.3   OC.sub. 7 H.sub.7                                                                        CH.sub.3                                    CH.sub.3    OC.sub.7 H.sub.7                                                                         CH.sub.3   CH.sub.3                                    H           i-C.sub.3 H.sub.7                                                                        OC.sub.7 H.sub.7                                                                         i-C.sub.3 H.sub.7                           ______________________________________                                    

preparation h 5-benzyloxy-4-Methoxy-2-Nitrobenzaldehyde

To concentrated nitric acid (200 ml.) maintained at 0° C. is added3-benzyloxy-4-methoxybenzaldehyde (48 g., 0.198 mole) over a 30 minuteperiod with stirring. When addition is complete, the temperature isallowed to rise to 15° C. and stirring continued for another 30 minutes.The mixture is then added to ice-water and the yellow precipitatecollected by filtration and dried. Yield = 52.8g. (94%); m.p. 131°-132°C.

In like manner, the products of Preparation G are nitrated to their2-nitro derivatives. In those cases wherein a mixture of products isobtained the products are separated by chromatography on an acid-washedsilica using an appropriate solvent such as benzene or chloroform.

What is claimed is:
 1. A compound selected from the group consisting of##STR34## and the pharmaceutically-acceptable cationic salts thereofwherein R is selected from the group consisting of methyl, ethyl, acetyland COR° whereinR^(o) is selected from the group consisting of hydroxy,alkoxy having 1 to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbonatoms, amino and hydroxyamino; each of R₂, R₃ and R₄ is selected fromthe group consisting of hydrogen, alkyl having 1 to 4 carbon atoms,alkoxy having 1 to 4 carbon atoms, halo, benzyloxy, hydroxy, thiol,alkanoyloxy having 1 to 4 carbon atoms, benzylthio, benzoyloxy,benzylsulfinyl, methylthio and methylsulfinyl and R₂ and R₃ , and R₃ andR₄ when taken together are selected from the group consisting ofmethylenedioxy and ethylenedioxy.
 2. A compound according to claim 1wherein each of R₂, R₃ and R₄ is hydrogen; and R is COR^(O) whereinR^(O) is said alkoxy.
 3. A compound according to claim 1 wherein R₂ ishydrogen; each of R₃, and R₄ is said alkoxy; and R is COR^(O) whereinR^(O) is said alkoxy.
 4. A compound according to claim 1 wherein R₂ ishydrogen; each of R₃ and R₄ is said alkyl; and R is COR^(O) whereinR^(O) is said alkoxy.
 5. A compound according to claim 2 wherein R^(O)is ethoxy.
 6. A compound according to claim 3 wherein R.sup. is ethoxy;and each of R₃ and R₄ is methoxy.
 7. A compound according to claim 4wherein R^(O) is ethoxy; and each of R₃ and R₄ is methyl.
 8. The methodof controlling allergic symptoms in a mammalian subject which comprisesadminstering to the subject an allergy symptom controlling amount of acompound selected from the group consisting of ##STR35## and thepharmaceutically-acceptable cationic salts thereof wherein R is selectedfrom the group consisting of methyl, ethyl, acetyl, and -COR^(O) whereinR^(O) is selected from the group consisting of hydroxy, alkoxy having 1to 4 carbon atoms. hydroxyalkoxy having 2 to 4 carbon atoms, amino andhydroxyamino;each of R₂, R₃ and R₄ is selected from the group consistingof hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4carbon atoms, halo, benzyloxy, hydroxy, thiol, alkanoyloxy having 1 to 4carbon atoms, benzylthio, benzylsulfinyl, benzoyloxy, methylthio, andmethylsulfinyl and R₂ and R₃, and R₃ and R₄ when taken together areselected from the group consisting of methylenedioxy and ethylenedioxy.9. The method of claim 8 wherein each of R₂, R₃ and R₄ is hydrogen and Ris COR^(O) wherein R^(O) is said alkoxy.
 10. The method of claim 8wherein R₂ is hydrogen, each of R₃ and R₄ is said alkyl; and R isCOR^(O) wherein R^(O) is said alkoxy.
 11. The method of claim 10 whereineach of R₃ and R₄ is methyl; and R^(O) is ethoxy.
 12. A pharmaceuticalcomposition active as an antiallergy agent comprising a compoundselected from the group consisting of ##STR36## and thepharmaceutically-acceptable cationic salts thereof wherein R is selectedfrom the group consisting of methyl, ethyl, acetyl and COR^(O) whereinR^(O) is selected from the group consisting of hydroxy, alkoxy having 1to 4 carbon atoms, hydroxyalkoxy having 2 to 4 carbon atoms andhydroxyamino;each of R₂, R₃ and R₄ is selected from the group consistingof hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4carbon atoms, halo, benzyloxy, hydroxy, thiol, alkanoyloxy having 1 to 4carbon atoms, bezylthio, benzoyloxy, benzylsulfinyl, methythio, andmethylsulfinyl; R₂ and R₃, and R₃ and R₄ when taken together areselected from the group consisting of methylenedioxy and ethylenedioxy;and a pharmaceutical carrier, said antiallergy agent being present in anamount of from about 0.5% to about 95% by weight of the carrier.
 13. Apharmaceutical composition as claimed in claim 12 in a form suitable foradministration by inhalation.
 14. A pharmaceutical composition asclaimed in claim 12 comprising a solution or suspension of theantiallergy agent in water.
 15. A pharmaceutical composition as claimedin claim 12 comprising a suspension of the antiallergy agent in aliquefied propellant.
 16. A pharmaceutical composition as claimed inclaim 12 comprising the solid antiallergy agent and a solid diluent.